Phenanthridinones as parp inhibitors

ABSTRACT

A compound of the formula (I): wherein ring A is a carbocyclic group, R1 is hydrogen or a halogen atom or a lower alkyl group, R2 is a di(lower)alkylamino group or N-containing heterocyclic group, among which the N-containing heterocyclic group may be substituted with one or more substituent(s), Y is an oxygen or sulfur atom, n is an integer from 0 to 2, and m is an integer from 0 to 4, or its prodrug, or their salt which has poly(adenosine 5′-diphospho-ribose)polymerase inhibiting activity.

TECHNICAL FIELD

This invention relates to novel tricyclic compounds having apharmacological activity, a process for their production and apharmaceutical composition containing the same.

BACKGROUND ART

Poly(adenosine 5′-diphospho-ribose)polymerase (hereinafter called asPARP) is an enzyme located in the nuclei of cells of various organs,including muscle, heart and brain cells. After recognizing strand breaksof DNA caused by NMDA(N-methyl-D-aspartate), NO, active oxygen and thelike, PARP catalyzes the attachment reaction of ADP-ribose units ofnicotinamide adenine dinucleotide (NAD) to a variety of nuclearproteins, including histones and PARP itself. However, excess activationof PARP leads to depletion of NAD and ATP in cells to induce cell death.Therefore, the PARP inhibitors are expected to be useful in treatmentand prevention of various diseases ascribed by NMDA- and NO-inducedtoxicity.

Some benimidazole derivatives having inhibitory activity of PARP havebeen known, for example, in WO00/29384, WO00/32579, WO00/68206 andWO01/21615.

DISCLOSURE OF INVENTION

An object of this invention is to provide novel tricyclic compounds,particularly phenanthridiones and tetrahydrophenanthridinones, and saltsthereof.

Another object of this invention is to provide a process for theproduction of the tricyclic compounds and salts thereof.

A further object of this invention is to provide a pharmaceuticalcomposition containing an effective amount of the tricyclic compound,its prodrug or a pharmaceutically acceptable salt thereof, which has aPARP inhibiting activity, as an active ingredient in admixture of apharmaceutically acceptable carrier.

Still further object of this invention is to provide a use of thetricyclic compound, its prodrug or a pharmaceutical acceptable saltthereof for preparing a medicament for treating or preventing diseasesascribed by excess activation of PARP.

Still further object of the invention is to provide a method of treatingor preventing diseases ascribed by excess activation of PARP byadministering the tricyclic compound, its prodrug or a pharmaceuticalacceptable salt thereof in an effective amount to inhibit PARP activity.

The tricyclic compounds of this invention are represented by thefollowing formula (I):

wherein

-   -   ring A is a carbocyclic group,    -   R¹ is hydrogen or a halogen atom or a lower alkyl group,    -   R² is a di(lower)alkylamino group or N-containing heterocyclic        group, among which the N-containing heterocyclic group may be        substituted with one or more substituent(s),    -   Y is an oxygen or sulfur atom,    -   n is an integer from 0 to 2, and    -   m is an integer from 0 to 4.

Suitable examples and illustrations of the above definitions areexplained in detail as follows.

The term “lower” means a group having 1 to 6 carbon atom(s), unlessotherwise provided.

The term “one or more” means 1 to 6, preferably 1 to 3, and morepreferably 1 or 2.

Suitable examples of the lower alkyl group and the lower alkyl moiety inthe di(lower)alkylamino group are straight or branched ones having 1 to6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,2-ethylbutyl, isobutyl, tert-butyl, pentyl, n-hexyl, etc.

Suitable examples of the halogen atom are fluorine, chlorine, bromine oriodine.

Suitable examples of the carbocyclic group are cyclo(lower)alkane ring(e.g., cyclobutane, cyclopentane, cyclohexane or cycloheptane),cyclo(lower)alkene ring (e.g., cyclopentene or cyclohexene) and aromatichydrocarbon ring (e.g., benzene or naphthalene).

Suitable examples of the N-containing heterocyclic group are monocyclicor condensed heterocyclic groups containing 1 to 4 nitrogen atom(s) andoptionally 1 to 2 oxygen or sulfur atom.

Preferable examples of the N-containing heterocyclic group are:

-   -   (1) unsaturated 3 to 7-membered, preferably 5- or 6-membered        heteromonocyclic group containing 1 to 4 nitrogen atoms, for        example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,        tetrahydropyridyl, pyrimidinyl, tetrahydropyrimidinyl,        pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,        1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl) or tetrazolyl (e.g.,        1H-tetrazolyl or 2H-tetrazolyl),    -   (2) saturated 3 to 7-membered, preferably 5- or 6-membered        heteromonocyclic group containing 1 to 4 nitrogen atoms, for        example, pyrrolidinyl, imidazolidinyl, piperidyl or piperazinyl,    -   (3) unsaturated 3 to 7-membered, preferably 5- or 6-membered        heteromonocyclic group containing 1 to 3 nitrogen atoms and 1 to        2 oxygen atoms, for example, oxazolyl, isoxazolyl or oxadiazolyl        (e.g., 1,2,4-oxadiazolyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolyl        or 1,2,5-oxadiazolyl);    -   (4) saturated 3 to 7-membered, preferably 5- or 6-membered        heteromonocyclic group containing 1 to 3 nitrogen atoms and 1 to        2 oxygen atoms, for example, morpholinyl,    -   (5) unsaturated 3 to 7-membered, preferably 5- or 6-membered        heteromonocyclic group containing 1 to 3 nitrogen atoms and 1 to        2 sulfur atoms, for example, thiazolyl or thiadiazolyl (e.g.,        1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl),    -   (6) saturated 3 to 7-membered preferably 5- or 6-membered        heteromonocyclic group containing 1 to 3 nitrogen atoms and 1 to        2 sulfur atoms, for example, thiomorpholinyl or thiazolidinyl,    -   (7) unsaturated condensed heterocyclic group containing 1 to 3        nitrogen atoms, for example, benzopyrrolyl, benzimidazolyl,        benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl,        indolinyl, isoindolidinyl, 1,2,3,4-tetrahydroquinolyl or        pyrido[3,4-b]indolyl,    -   (8) unsaturated condensed heterocyclic group containing 1 to 3        nitrogen atoms and 1 to 2 oxygen atoms, for example,        benzoxazolyl, benzoxadiazolyl or phenoxazinyl; or    -   (9) unsaturated condensed heterocyclic group containing 1 to 3        nitrogen atoms and 1 to 2 sulfur atoms, for example,        benzothiazolyl, benzisothiazolyl or phenothiazinyl.

Among the above, more preferable heterocyclic group is an unsaturated 5-or 6-membered heteromonocyclic group as mentioned in the above (1) or asaturated 5- or 6-membered heteromonocyclic group as mentioned in theabove (2) and (4), among which the most preferable one is pyridyl,tetrahydropyridyl, piperidyl, piperazinyl or morpholinyl.

The N-containing heterocyclic group and1,3,4,9-tetrahydro-2H-β-carbolin-2-yl group may be optionallysubstituted with one or more substituent(s) such as hydroxy; amino;carboxy; cyano; nitro; carbamoyl; oxo; halogen (e.g., fluorine, bromineor chlorine); lower alkyl (e.g., methyl, ethyl, isopropyl ortert-butyl); lower alkoxy (e.g., methoxy, ethoxy, butoxy or n-propoxy);halo(lower)alkyl (e.g., chloromethyl or trifluoromethyl); optionallysubstituted aryl [e.g., naphthyl or phenyl which may be furthersubstituted with halogen (e.g., fluorine, bromine or chlorine), loweralkoxy (e.g., methoxy, ethoxy, butoxy or n-propoxy), cyano orhalo(lower)alkyl (e.g., chloromethyl or trifluoromethyl)]; aryloxy(e.g., phenoxy); or aroyl (e.g., benzoyl).

Suitable salts of the compound (I) are pharmaceutically acceptable,conventional and non-toxic salts, for example an organic acid additionsalt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate,oxalate, methanesulfonate, benzenesulfonate or toluenesulfonate), aninorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfateor phosphate), a salt with an amino acid (e.g. aspartate or glutamate),or the like.

The compounds (I) may contain one or more asymmetric centers and thusthey can exist as enantiomers or diastereoisomers.

The compounds (I) may also exist in tautomeric forms and the inventionincludes both mixtures and separate individual tautomers.

The compound (I) and its salt can be in a form of a solvate, which isalso included within the scope of the present invention. The solvatepreferably include a hydrate and an ethanolate.

Also included in the scope of invention are radiolabelled derivatives ofcompounds (I) which are suitable for biological studies.

The “prodrug” may be a derivative of the compound (I) having achemically or metabolically degradable group, which becomespharmaceutically active substance after biotransformation.

Preferred compounds (I) are the ones ring A is a cyclo(lower)alkane ringor aromatic hydrocarbon ring,

-   -   R¹ is hydrogen or a halogen atom,    -   n is an integer of 0 or 1, and    -   R², Y and m have the same meaning as defined in the above.

More preferred compounds (I) are the ones wherein R² is tetrazolyl,pyridyl, piperidyl, piperazinyl, morpholinyl, isoindolidinyl orpyrido[3,4-b]indolyl, each of which may be substituted with one or moresubstituent(s).

Further preferred compounds (I) are the ones wherein the ring A is acyclohexane ring,

-   -   R¹ is hydrogen atom, and    -   R², Y, n and m have the same meaning as defined in the above,        and    -   the ones wherein the ring A is a benzene ring,    -   R¹ is hydrogen or a halogen atom,    -   R² and Y have the same meaning as defined in the above,    -   n is 0, and    -   m is an integer 3 or 4.

Especially preferred compounds (I) are those wherein the ring A is acyclohexane ring,

-   -   R¹ is hydrogen atom,    -   R² has the same meaning as defined in the above,    -   Y is an oxygen atom,    -   n is an integer of 0 or 1, and    -   m is an integer from 0 to 3.

The compound (I) or a salt thereof can be prepared by the followingprocesses.

wherein, R¹, R², Y, n, m and the ring A are each as defined above, X isa leaving group, R³ and R⁴ are each lower alkyl group, Y¹s areindependently a hydroxy group or oxygen atom and/or together representan oxo group or ethylene ketal or propylene ketal group,

is a N-containing heterocyclic group or1,3,4,9-tetrahydro-2H-β-carbolin-2-yl group, both of which may beoptionally substituted with one or more substituent(s),

is a N-containing heterocyclic group which may be optionally substitutedwith one or more substituent(s),

is a tetrazolyl group.

Suitable leaving group may be halogen (e.g., fluoro, chloro, bromo oriodo), arylsulfonyloxy (e.g., benzenesulfonyloxy or tosyloxy),alkylsulfonyloxy (e.g., mesyloxy or ethanesulfonyloxy) or the like,among which the preferable one is halogen.

PROCESS 1

The object compound (I-1) or its salt can be prepared by reacting acompound (II) or its salt with a compound (III-1) or its salt.

This reaction is usually carried out in the presence of an inorganic oran organic base. Suitable inorganic base may be an alkali metal [e.g.,sodium or potassium], an alkali metal hydroxide [e.g., sodium hydroxideor potassium hydroxide], alkali metal hydrogen carbonate [e.g., sodiumhydrogen carbonate or potassium hydrogen carbonate], alkali metalcarbonate [e.g., sodium carbonate or potassium carbonate], alkalineearth metal carbonate [e.g., calcium carbonate or magnesium carbonate],alkali metal hydride [e.g., sodium hydride or potassium hydride], or thelike. Suitable organic base may be tri(lower)alkylamine [e.g.,triethylamine or N,N-diisopropylethylamine], alkyl magnesium bromide[e.g., methyl magnesium bromide or ethyl magnesium bromide], alkyllithium [e.g., methyl lithium or butyl lithium], lithiumdiisopropylamide, lithium hexamethyldisilazido, or the like.

The reaction is usually carried out in a conventional solvent such as analcohol [e.g., methanol, ethanol, propanol or isopropanol], aromatichydrocarbon [e.g., benzene, toluene or xylene], ethyl acetate,acetonitrile, dioxane, chloroform, methylene chloride,N,N-dimethylformamide or any other organic solvent which does notadversely influence the reaction.

The reaction temperature is not critical , and the reaction is usuallycarried out under cooling to heating.

PROCESS 2

The object compound (I-2) or its salt can be prepared by reacting acompound (IV) or its salt with a compound (III-2) or its salt.

This reaction is usually carried out in the presence of an inorganic ororganic base, a binaphthyl compound and palladium catalyst. Suitableinorganic base may be an alkali metal alkoxide [e.g., sodium methoxide,potassium ethoxide or sodium tert-butoxide], or the like. Suitablebinaphthyl compound may be 2,2′-bis(diphenylphophino)-1,1′-binaphthyl.Suitable palladium compound may be tris(dibenzylideneacetone)dipalladium(0).

The reaction is usually carried out in a conventional solvent such asaromatic hydrocarbon [e.g., benzene, toluene or xylenel, ethyl acetate,acetonitrile, dioxane, N,N-dimethylformamide or any other organicsolvent which does not adversely influence the reaction.

The reaction is usually carried out at the temperature higher than 100°C., preferably around 140° C. in a sealed tube.

PROCESS 3

The object compound (I-3) or its salt can be prepared by reacting acompound (IV) or its salt with a compound (III-3) or its salt in asimilar manner to the above Process 2.

PROCESS 4

The object compound (I-4) or its salt can be prepared by reacting acompound M or its salt with a compound (VI) or its salt.

This reaction is usually carried out in the presence of an inorganic oran organic base. Suitable inorganic base and organic base are the sameas those exemplified in the above Process 1.

The reaction is usually carried out in a conventional solvent such as analcohol [e.g., methanol, ethanol, propanol or isopropanol], aromatichydrocarbon [e.g., benzene, toluene or xylene], ethyl acetate,acetonitrile, dioxane, chloroform, methylene chloride,N,N-dimethylformamide, dimethylsulfoxide or any other organic solventwhich does not adversely influence the reaction.

The reaction is usually carried out at the temperature higher than 100°C., preferably around 130° C.

PROCESS 5

The object compound (I-1) or its salt can be prepared by reacting acompound (VII) or its salt with a compound (III-1) or its salt in asimilar manner to the above Process 1 and then treating withhydrochloric acid.

PROCESS 6

The object compound (I-5) or its salt can be prepared by reacting acompound (VIII) or its salt with a trialkyl orthoformate and an azidecompound.

The reaction can be carried out in a conventional organic acid such asacetic acid or propionic acid under heating.

PROCESS 7

The object compound (I-6) can be prepared by reacting a compound (IX)with a 3-fluorophthalic anhydride and then treating the reaction productwith perchloric acid, and then with sulfuric acid.

The reaction can be carried out in a halogenated solvent such asmethylene chloride, chloroform, carbon tetrachloride,1,2-dicholoroethane, at a temperature cooling to heating.

Thus obtained compounds (I-1), (I-2), (I-3), (I-4), (I-5) and (I-6) canbe purified by a conventional purification method such asrecrystallization, column chromatography, thin-layer chromatography,high-performance liquid chromatography or the like. The compound (I) canbe identified by a conventional method such as NMR spectrography, massspectrography, infrared spectrography, elemental analysis, ormeasurement of melting point.

Starting compounds (II), (III-1), (III-2), (III-3), (III-4), (IV), (V),(VI), (VII), (VIII) and (IX) are commercially available or can beprepared by the well-known processes, for example, the processesdescribed in M. P. Hay and W. A. Denny, Synthetic Communication, 28(3),463-470, 1998 or analogous processes thereof.

In order to illustrate the utility of the compound (I), thepharmacological test of the compound (I) is explained in the following.

PARP inhibitory activity (In vitro assay)

(1) Assay method:

The recombinant human PARP (5.3 mg protein/ml) was incubated with a testcompound in a 100 μl reaction buffer containing an indicatedconcentration of 1 mCi/ml ³²P-NAD, 50 mM Tris-HCl, 25 mM MgCl₂, 1 mM DTT(dithiothreitol), 0.05 mM NAD (nicotinamide adenine dinucleotide) and 1mg/ml activated DNA, pH8.0. Incubation was carried out for 15 minutes ata room temperature, and the reaction was stopped by addition of 200 μlof ice-cold 20% tricholoroacetic acid followed by rapid filtrationthrough GF/B filters. The filtrate was treated with scintillation fluidand acid-insoluble counts were measured for quantification of unitactivity. PARP inhibitory activity was calculated by using the followingformula: PARP inhibitory activity (%)=[1-(count obtained with testcompound)/(count obtained with vehicle only)]×100

(2) Results TABLE 1 PARP inhibitory activity (IC₅₀) of the testcompound. Test Compound IC₅₀(nM) Example 2 <100 Example 15 <100 Example30 <100 Example 35 <100 Example 42 <100 Example 52 <100 Example 60 <100Example 63 <100

The compounds (I) have a potent PARP inhibitory activity as shown in theabove. PARP inhibitors of this invention were effective in preventingreduction of striatal DA(dopamine) and its metabolite induced by MPTP(N-methyl-1,2,3,6-tetrahydropyridine) treatment in mice. Therefore, itis suggested that these compounds may have protective benefit in thetreatment of neurodegenerative disease such as Parkinson's disease.

It has been known that, during major cellular stresses, the activationof PARP can rapidly lead to cell damage or death through depletion ofenergy stores and PARP activation play a key role in both NMDA- andNO-induced neurotoxicity (Zhang et. al., Science, 263: 687-89 (1994)).Therefore, the compound (I) of this invention and a pharmaceuticallyacceptable salt thereof possessing PARP inhibiting activity are usefulin treating and preventing various diseases ascribed by NMDA- andNO-induced toxicity. Such diseases include, for example, tissue damageresulting from cell damage or death due to necrosis or apoptosis; neuraltissue damage resulting from ischemia and reperfusion injury,neurological disorders and neurodegenerative diseases; neurodegenerativediseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease;epilepsy; amyotrophic lateral scleosis (ALS); Huntington's disease;schizophrenia; chronic pain; ischemia and neuronal loss followinghypoxia; hypoglycemia; ischemia; trauma; and nervous insult.

It has been demonstrated that PARP inhibitor is useful in reducinginfarct size (Thiemermann et al, Proc. Natl. Acad. Sci. USA, 94: 679-83(1997)). Therefore, the compound (I) of this invention and apharmaceutically acceptable salt thereof possessing PARP inhibitingactivity are useful in treatment and prevention of previously ischemicheart or skeleton muscle tissue.

It is also known that PARP is thought to play a role in enhancing DNArepair. So, the compound (I) of this invention and a pharmaceuticallyacceptable salt thereof possessing PARP inhibiting activity areeffective in treating and preventing radiosensitizing hypoxic tumorcells; tumor cells from recovering from potentially lethal damage of DNAafter radiation therapy.

Further, the compound (I) of this invention and a pharmaceuticallyacceptable salt thereof possessing PARP inhibiting activity are usefulin extending the life-span and proliferative capacity of cells andaltering gene expression of senescent cells. They are useful fortreating and preventing skin aging; Alzheimer's diseases;atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy;degenerative diseases of skeletal muscle involving replicativesenescence; age-related macular degeneration; immune senescence; AIDS;and other immune senescence diseases.

Still further, the compound (I) of this invention and a pharmaceuticallyacceptable salt thereof possessing PARP inhibiting activity areeffective in treating and preventing inflammatory bowel disorders (e.g.,colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor.Also, the compounds (I) are useful in reducing proliferation of tumorcells and making synergistic effect when tumor cells are co-treated withan alkylating drug.

The compound (I) of this invention and a pharmaceutically acceptablesalt thereof possessing PARP inhibiting activity are effective intreating and preventing pituitary apoplexy; conjunctivitis;retinoblastoma; retinopathy; acute retinal necrosis syndrome; Sjogren'ssyndrome.

Accordingly, the present invention provides a method for treating orpreventing diseases ascribed by NMDA- and NO-induced toxicity byadministering a compound (I), its prodrug, or a pharmaceuticallyacceptable salt thereof in an effective amount to inhibit PARP activity,to a human being or an animal who needs to be treated or prevented.

The compound (I), its prodrug or their salt can be administered alone orin the form of a mixture, preferably, with a pharmaceutical vehicle orcarrier. Accordingly, the present invention provides a pharmaceuticalcomposition comprising a compound (I), its prodrug or a pharmaceuticallyacceptable salt thereof as an active ingredient in admixture with apharmaceutically acceptable carrier such as an organic or inorganiccarrier or excipient suitable for external (topical), enteral,intravenous, intramuscular, parenteral or intramucous applications in apharmaceutical preparation, for example, in solid, semisolid or liquidform.

The compound (I), its prodrug or a pharmaceutical acceptable saltthereof can be formulated, for example, with the conventional non-toxic,pharmaceutically acceptable carriers for ointment, cream, plaster,tablets, pellets, capsules, suppositories, solution (saline, forexample), emulsion, suspension (olive oil, for example), aerosols,pills, powders, syrup, injection, troches, cataplasms, aromatic water,lotion, buccal tablets, sublingual tablets, nasal drop or any other formsuitable for use. The carriers which can be used are water, wax,glucose, lactose, gum acacia, gelatin, mannitol, starch paster,magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidalsilica, potato starch, urea and other carriers suitable for use inmanufacturing preparations, in solid, semisolid, or liquid form, and inaddition to the above auxiliary, stabilizing, thickening or coloringagent and perfume may be used.

The compound (I), its prodrug or a pharmaceutical acceptable saltthereof can be formulated into, for example, preparations for oralapplication, preparations for injection, preparations for externalapplication, preparations for inhalation, preparations for applicationto mucous membranes.

The present invention provides a pharmaceutical composition containing acompound (I), its prodrug or a pharmaceutical acceptable salt thereof inadmixture of a pharmaceutically acceptable salt for treating orpreventing diseases ascribed by NMDA- and NO-induced toxicity,specifically for extending the lifespan or proliferative capacity ofcells or altering gene expression of senescent cells, more specificallyfor treating or preventing diseases ascribed by excess activation ofPARP such as tissue damage resulting from cell damage or death due tonecrosis or apoptosis; neural tissue damage resulting from ischemia andreperfusion injury, neurological disorders and neurodegenerativediseases; neurodegenerative diseases; head trauma; stroke; Alzheimer'sdisease; Perkinson's disease; epilepsy; Amyotrophic Lateral Scleosis(ALS); Huntington's disease; schizopherenia; chronic pain; ischemia andneuronal loss following hypoxia; hypoglycemia; ischemia; trauma; nervousinsult; previously ischemic heart or skeleton muscle tissue;radiosensitizing hypoxic tumor cells; tumor cells from recovering frompotentially lethal damage of DNA after radiation therapy; skin aging;atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy;degenerative diseases of skeletal muscle involving replicativesenescence; age-related macular degeneration; immune senescence; AIDS;and other immune senescencediseases; inflammatory bowel disorders (e.g.,colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor.

Mammals which may be treated by the present invention include livestockmammals such as cows, horses, etc., domestic animals such as dogs, cats,rats, etc. and human beings, preferably human beings.

While the dosage of therapeutically effective amount of the compound (I)varies depending on the age and condition of each individual patient, anaverage single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective fortreating the above-mentioned diseases. In general, amounts between 0.01mg/body and about 1,000 mg/body may be administered per day.

Any patents, patent applications, and publications cited herein areincorporated by reference.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Preparation and Examples are given for the purpose ofillustrating the present invention in detail, but are not to beconstrued to limit the scope of the present invention.

Abbreviations used in the following Examples are as follows:

-   AcOH: acetic acid-   DCM: dichloromethane-   DMF: N,N-dimethylformamide-   EtOAc: ethyl acetate-   MeOH: methanol-   THF: tetrahydrofuran

REFERENCE EXAMPLE 1

Under ice cooling, ethyl chloroformate (8.04 g) was added over 30minutes to a solution of 3-(4-aminophenyl)propanoic acid (10.2 g) in 50%aqueous THF (100 ml) while pH of the solution was maintained between 8and 10. The solution was stirred for 30 minutes under ice cooling andthen sodium chloride (30 g) and EtOAc (50 ml) was added to the solution.The organic layer was separated. The aqueous layer was acidified with10% aqueous hydrogen chloride and extracted with EtOAc. The combinedorganic layer was washed with brine, dried over magnesium sulfate andevaporated to give 3-{4-[(ethoxycarbonyl)amino]phenyl}-propanoic acid(10.2 g). ¹H-NMR (DMSO-d₆) δ: 1.23(3H, t, J=7.1 Hz), 2.4-2.6(2H, m),2.7-2.8(2H, m), 4.10(2H, q, J=7.1 Hz), 7.07(2H, d, J=8.5 Hz), 7.34(2H,d, J=8.5 Hz), 9.49(1H, s).

Mass: 236.27 (M-H)−.

REFERENCE EXAMPLE 2

Ethyl 4-(4-hydroxybutyl)phenylcarbamate was obtained in a similar mannerto Reference Example 1.

¹H-NMR (DMSO-d₆) δ: 1.23(3H, t, J=7.1 Hz), 1.35-1.65(4H, m),2.45-2.55(2H, m), 3.3-3.45(2H, m), 4.10(2H, q, J=7.1 Hz), 4.33(1H, t,J=5.2 Hz), 7.07(2H, d, J=8.5 Hz), 7.34(2H, d, J=8.5 Hz), 9.46(1H, s)

Mass: 260.2 (M+Na)+.

REFERENCE EXAMPLE 3

Bromine (3.51 g) was added to a solution of ethyl4-(3-hydroxypropyl)phenylcarbamate (4.46 g) and sodium acetate (3.28 g)in AcOH (50 ml), and the mixture was stirred for 5 hours. Afterevaporation of the solvent, the residue was diluted with a mixture ofwater and EtOAc. The separated organic layer was washed with an aqueoussaturated sodium hydrogencarbonate solution, an aqueous sodiumthiosulfate solution and brine, successively and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified bycolumn chromatography on silica-gel eluting with a mixture of n-hexaneand EtOAc to give ethyl 2-bromo-4-(3-hydroxypropyl)phenylcarbamate (5.53g).

¹H-NMR (DMSO-d₆) δ:1.32(3H, t, J=7.1 Hz), 1.8-2.0(2H, m), 2.65(2H, t,J=7.2 Hz), 3.6-3.7(2H, m), 4.23(2H, q, J=7.1 Hz), 7.02(1H, br s),7.13(1H, dd, J=8.4, 2.0 Hz), 7.35(1H, d, J=2.0 Hz), 8.01(1H, d, J=8.4Hz).

Mass: 303.67 (M+H)+.

REFERENCE EXAMPLE 4

Ethyl 2-bromo-4-(4-hydroxybutyl)phenylcarbamate was obtained in asimilar manner to Reference Example 3. ¹H-NMR (CDCl₃) δ: 1.32(3H, t,J=7.1 Hz), 1.4-1.8(5H, m), 2.58(2H, t, J=7.1 Hz), 3.65(2H, t, J=6.3 Hz),4.24(2H, q, J=7.1 Hz), 7.01(1H, s), 7.11(1H, dd, J=8.4, 2.0 Hz),7.33(1H, d, J=2.0 Hz), 8.00(1H, d, J=8.4 Hz).

Mass: 338.1, 340.1 (M+Na)+.

REFERENCE EXAMPLE 5

Under a nitrogen atmosphere, phosphorus tribromide (0.57 ml) was addedto a solution of ethyl 2-bromo-4-(3-hydroxypropyl)phenyl-carbamate (5.2g) in EtOAc (50 ml) at −20° C. The mixture was stirred for 1 hour underice cooling. After the ice bath was removed, the mixture was stirredovernight at ambient temperature. The mixture was poured into a mixtureof an aqueous saturated sodium hydrogen carbonate solution and EtOAc.The separated organic layer was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography on silica-gel eluting with a mixtureof n-hexane and EtOAc to give ethyl

2-bromo-4-(3-bromopropyl)phenylcarbamate (4.1 g). ¹H-NMR (CDCl₃) δ:1.33(3H, t, J=7.1 Hz), 2.0-2.0(2H, m), 2.65-2.8(2H, m), 3.37(2H, t,J=6.5 Hz), 4.24(2H, q, J=7.1 Hz), 7.03(1H, br s), 7.13(1H, dd, J=8.4,2.0 Hz), 7.36(1H, d, J=2.0 Hz), 8.04(1H, d, J=8.4 Hz).

Mass: 388.0 (M+Na)+.

REFERENCE EXAMPLE 6

The following compounds (1) and (2) were obtained in a similar manner toReference Example 5.

(1)

Ethyl 2-bromo-4-(4-bromobutyl)phenylcarbamate ¹H-NMR (CDCl₃) δ: 1.33(3H,t, J=7.1 Hz), 1.65-2.0(4H, m), 2.57(2H, t, J=7.1 Hz), 3.41(2H, t, J=6.1Hz), 4.24(2H, q, J=7.1 Hz), 7.02(1H, br s), 7.11(1H, dd, J=8.2, 2.0 Hz),7.32(1H, d, J=2.0 Hz), 8.02(1H, d, J=8.4 Hz).

Mass: 400.0, 402.0 (M+Na)+.

(2)

N-[3-(Bromomethyl)phenyl)-1,4-dioxaspiro[4.5]decane-6-carboxamide

¹H-NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.7(1H, m), 3.7-4.1(4H, m),4.52(2H, s), 6.97(1H, d, J=7.8 Hz), 7.24(1H, t, J=7.8 Hz), 7.43(1H, d,J=7.8 Hz), 7.76(1H, s), 9.72(1H, s).

REFERENCE EXAMPLE 7

Under a nitrogen atmosphere, phenylboronic acid (437 mg), 2M aqueoussolution of sodium dicarbonate (4.5 ml) andtetrakis(triphenylphosphine)palladium (0) (173 mg) were added to asolution of ethyl 2-bromo-4-(3-bromopropyl)phenylcarbamate (1.1 g) indimethoxyethane (13.5 ml) at room temperature. The mixture was refluxedfor 5 hours. After cooling to room temperature, the mitre was pouredinto a mixture of water and EtOAc. The separated organic layer waswashed with brine and dried over magnesium sulfate. After evaporation ofthe solvent, the residue was purified by column chromatography onsilica-gel eluting with toluene to give ethyl5-(3-bromopropyl)-1,1′-biphenyl-2-ylcarbamate (1.1 g).

¹H-NMR (CDCl₃) δ: 1.24(3H, t, J=7.1 Hz), 2.0-2.4(2H, m), 2.76(2H, t,J=7.0 Hz), 3.40(2H, t, J=6.6 Hz), 4.16(2H, q, J=7.1 Hz), 6.55(1H, br s),7.0-7.5(7H, m), 8.02(1H, d, J=8.3 Hz).

Mass: 384.1, 386.1 (M+Na)+.

REFERENCE EXAMPLE 8

The following compounds described in (1) and (2) were obtained in asimilar manner to Reference Example 7.

(1)

Ethyl 5-(3-bromopropyl)-4′-chloro-1,1′-biphenyl-2-ylcarbamate ¹H-NMR(CDCl₃) δ: 1.25(3H, t, J=7.1 Hz), 2.0-2.3(2H, m), 2.76(2H, t, J=7.0 Hz),3.3-3.5(2H, m), 4.16(2H, q, J=7.1 Hz), 6.41(1H, br s), 6.7-7.5(6H, m),7.98(1H, d, J=8.0 Hz).

Mass: 418.1, 420.1 (M+Na)+.

(2)

Ethyl 5-(4-bromobutyl)-1,1′-biphenyl-2-ylcarbamate ¹H-NMR (CDCl₃) δ:1.24(3H, t, J=7.2 Hz), 1.65-2.0(4H, m), 2.55-2.75(2H, m), 3.41(2H, q,J=7.0 Hz), 4.16(2H, q, J=7.2 Hz), 6.53(1H, br s), 7.0-7.5(7H, m),8.01(1H, d, J=8.3 Hz).

Mass: 398.1, 400.2 (M+H)+.

REFERENCE EXAMPLE 9

Under a nitrogen atmosphere, phosphorus pentoxide (511 mg) was added toa solution of ethyl 5-(3-bromopropyl)-1,1′-biphenyl-2-ylcarbamate (435mg) in phosphorus oxychloride (3 ml) at room temperature. The mire wasrefluxed for 2 hours. After evaporation of the solvent, the residue waspoured into a mixture of ice-water and EtOAc. The solution was broughtto pH 9 with 10% aqueous solution of potassium carbonate. The separatedorganic layer was washed with brine and dried over magnesium sulfate.After evaporation of the solvent in vacuo, the residue was dissolved ina mixture of dioxane (6 ml) and 4N aqueous hydrogen chloride (3 ml). Thesolution was refluxed for 30 minutes, cooled to room temperature andthen poured into a mixture of water and EtOAc. The mixture wasneutralized with 10% aqueous solution of potassium carbonate. Theseparated organic layer was washed with brine and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified bycolumn chromatography on silica-gel eluting with a mixture of DCM andacetone to give 2-(3-bromopropyl)-6(5H)-phenanthridinone (280 mg).

¹H-NMR (DMSO-d₆) δ: 2.0-2.3(2H, m), 2.83(2H, t, J=7.0 Hz), 3.5-3.7(2H,m), 7.25-7.4(2H, m), 7.63(1H, t, J=7.1 Hz), 7.85(1H, dt, J=7.2, 1.5 Hz),8.23(1H, s), 8.32(1H, dt, J=7.9, 1.2 Hz), 8.52(1H, d, J=8.1 Hz),11.62(1H, s).

Mass: 316.2, 318.2 (M+H)+.

REFERENCE EXAMPLE 10

The following compounds described in (1) and (2) were obtained in asimilar manner to Reference Example 9.

(1)

2-(3-Bromopropyl)-8-chloro-6(5H)-phenanthridinone ¹H-NMR (DMSO-d₆) δ:2.0-2.4(2H, m), 2.7-2.9(2H, m), 3.4-3.8(2H, m), 7.2-7.5(3H, m),7.8-7.95(1H, m), 8.2-8.3(2H, m), 8.57(1H, d, J=8.8 Hz), 11.79(1H, s).

Mass: 372.1, 374.1 (M+Na)+.

(2)

2-(4-Chlorobutyl)-6 (5H)-phenanthridinone ¹H-NMR (DMSO-d₆) δ:1.7-2.0(4H, m), 2.65-2.85(2H, m), 3.6-3.75(2H, m), 7.25-7.35(2H, m),7.55-7.7(1H, m), 7.8-7.9(1H, m), 8.21(1H, s), 8.3-8.4(1H, m), 8.52(1H,d, J=8.3 Hz), 11.61(1H, s).

Mass: 308.3 (M+Na)+.

REFERENCE EXAMPLE 11

A mixture of 50% Pd/C catalyst (50% wet, 2.72 g) and1-(4-hydroxybutyl)-4-nitrobenzene (5 g) in MeOH (50 ml) was stirredunder hydrogen at atmospheric pressure until hydrogen gas absorptionstopped. After filtration of the reaction mixture on celite, thefiltrate was concentrated in vacuo to give 4-(4-hydroxybutyl)aniline(4.0 g). ¹H-NMR (DMSO-d₆) δ: 1.3-1.6(4H, m), 2.38(2H, t, J=7.1 Hz),3.3-3.45(2H, m), 4.31(1H, t, J=5.2 Hz), 4.77(2H, s), 6.4-6.55(2H, m),6.75-6.9(2H, m).

Mass: 166.4 (M+H)+.

REFERENCE EXAMPLE 12

Under a nitrogen atmosphere, 4-nitrophenol (6.95 g) was addedportionwise to a solution of potassium tert-butoxide (6.73 g) in DMF (70ml) with ice cooling. After the mire was stirred for 5 minutes,bromochloroethane (7.88 g) was added to the mixture. The mixture wasstirred at ambient temperature for 30 minutes and then heated at 80° C.for 4 hours. The mixture was cooled to room temperature and poured intoa mixture of water and EtOAc. The separated organic layer was washedwith water and brine, successively and dried over magnesium sulfate.After evaporation of the solvent, the residue was purified by columnchromatography on silica-gel eluting with a mixture of n-hexane andEtOAc to give 1-(2-chloroethoxy)-4-nitrobenzene (4.37 g).

¹H-NMR (CDCl₃) δ: 3.85(2H, t, J=5.7 Hz), 4.33(2H, t, J=5.7 Hz),6.9-7.0(2H, m), 8.15-8.25(2H, m).

REFERENCE EXAMPLE 13

Ammonium chloride (430 mg) was added to a mixture of1-(2-chloroethoxy)-4-nitrobenzene (4.3 g) in THF (40 ml), ethanol (80ml) and water (12 ml). The mixture was gradually warmed to 50° C. andiron (reduced) (4.3 g) was added portionwise thereto. The whole mixturewas refluxed for 1 hour and then cooled to room temperature. Afterunsolvable material was removed by filtration on celite, the filtratewas concentrated in vacuo. The residue was diluted with EtOAc and theobtained solution was washed with water and brine, successively. Afterthe solution was dried over magnesium sulfate, the solution wasevaporated to give 4-(2-chloroethoxy)aniline (2.7 g). ¹H-NMR (CDCl₃) δ:3.76(2H, t, J=5.9 Hz), 4.15(2H, t, J=5.9 Hz), 6.5-6.85(4H, m).

REFERENCE EXAMPLE 14

3-(2-Bromoethyl)aniline hydrochloride was obtained in a similar mannerto Reference Example 13.

¹H-NMR (DMSO-d₆) δ: 3.16(2H, t, J=7.0 Hz), 3.74(2H, t, J=7.0 Hz),7.15-7.45(4H, m).

Mass: 200.1, 202.2(M+H)+.

REFERENCE EXAMPLE 15

4-(2-Chloroethoxy)aniline (1.72 g) was added to a solution of ethyl2-cyclohexanonecarboxylate (2.3 g) in xylene (4 ml). The mixture washeated at 190° C. for 1 hour and then cooled to room temperature. Thesolution was poured into a mixture of water and EtOAc The separatedorganic layer was washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue was dissolved in 90%sulfuric acid (8 ml). The solution was heated at 60° C. for 30 minutes,poured on ice and then stirred for 30 minutes. The resulting precipitatewas collected by filtration and dissolved in EtOAc. The organic solutionwas washed with water and brine, successively and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified bycolumn chromatography on silica-gel eluting with a mixture of DCM andacetone to give2-(2-chloroethoxy)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (220 mg).

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.6(2H, m), 2.7-2.8(2H, m),3.9-4.0(2H, m), 4.25-4.35(2H, m), 7.05-7.25(3H, m), 11.50(1H, s).

Mass: 300.1, 302.1(M+Na)+.

REFERENCE EXAMPLE 16

Under ice cooling, 10N THF solution of borane-methyl sulfide complex(2.35 ml) was added slowly to a solution of3-{4-[(tert-butoxycarbonyl)amino]phenyl}propanoic acid (5.2 g) in THF(50 ml). The ice bath was removed after 5 minutes of the addition. Themixture was stirred at ambient temperature for 1 hour. After thereaction was quenched with water, the mixture was poured into a mixtureof cold water and EtOAc. The mixture was brought to be basic with anaqueous saturated sodium hydrogencarbonate solution. The separatedorganic layer was washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue was purified by columnchromatography on silica-gel eluting with a mixture of DCM and acetoneto give tert-butyl 4-(3-hydroxypropyl)phenylcarbamate (4.6 g).

¹H-NMR (DMSO-d₆) δ: 1.46(9H, s), 1.6-1.8(2H, m), 2.45-2.65(2H, m),3.40(2H, q, J=6.4 Hz), 4.44(1H, t, J=5.2 Hz), 6.78(1H, d, J=7.2 Hz),7.12(1H, t, J=7.2 Hz), 7.21(1H, d, J=7.2 Hz), 7.33(1H, s), 9.22(1H, s).

Mass: 274.3(M+Na)+.

REFERENCE EXAMPLE 17

Ethyl 4-(3-hydroxypropyl)phenyl carbamate was obtained in a similarmanner to Reference Example 16.

¹H-NMR (CDCl₃) δ: 1.30(3H, t, J=7.1 Hz), 1.8-1.95(2H, m), 2.66(2H, t,J=7.2 Hz), 3.6-3.7(2H, m), 4.21(2H, q, J=7.1 Hz), 6.60(1H, br s),7.12(2H, d, J=8.6 Hz), 7.28(2H, d, J=8.6 Hz).

Mass: 246.3 (M+Na)+.

REFERENCE EXAMPLE 18

Under a nitrogen atmosphere, triethylamine (7.7 ml) and methanesulfonylchloride (1.6 ml) were added successively to a solution of tert-butyl4-(3-hydroxypropyl)phenylcarbamate (4.6 g) in DCM (50 ml) at −15° C. Themixture was stirred for 1 hour at the same temperature and then pouredinto a mixture of water and EtOAc. The separated organic layer waswashed with diluted aqueous hydrogen chloride and brine, successivelyand dried over magnesium sulfate. The organic layer was evaporated underreduced pressure to give 3-{4-[(tert-butoxycarbonyl)amino]phenyl}propylmethanesulfonate (6.5 g).

¹H-NMR (DMSO-d₆) δ: 1.46(9H, s), 1.9-2.0(2H, m), 3.61(2H, t, J=6.4 Hz),3.15(3H, s), 4.19(2H, t, J=6.4 Hz), 6.82(1H, d, J=7.2 Hz), 7.1-7.3(2H,m), 7.36(1H, s), 9.26(1H, s).

Mass: 328.2(M-H)−

REFERENCE EXAMPLE 19

Under a nitrogen atmosphere, sodium bromide (4.09 g) was added to asolution of 3-{4-[(tert-butoxycarbonyl)amino]phenyl}propylmethanesulfonate (6.54 g) in DMF (60 ml) at room temperature. Themixture was stirred for 2 hours at 60° C. and poured into a mixture ofwater and EtOAc. The separated organic layer was washed twice with waterand brine, successively and dried over magnesium sulfate. The organiclayer was evaporated to give tert-butyl 4-(3-bromopropyl)phenylcarbamate(5.30 g).

¹H-NMR (DMSO-d₆) δ: 1.46(9H, s), 2.0-2.2(2H, m), 2.5-2.7(2H, m),3.50(2H, t, J=6.6 Hz), 6.80(1H, d, J=7.3 Hz), 7.15(1H, t, J=7.3 Hz),7.25(1H, d, J=7.3 Hz), 7.35(1H, s), 9.26(1H, s).

Mass: 336.1, 338.2(M+Na)+

REFERENCE EXAMPLE 20

Trifluoroacetic acid (13 ml) was added to a solution of tert-butyl4-(3-bromopropyl)phenylcarbamate (5.25 g) in DCM at room temperature.The mixture was stirred for 4 hours. After evaporation of the solvent,diethyl ether was added to the residue to wash the crude product. Afterthe ethereal layer was removed by decantation, the resulting crude oilwas diluted with EtOAc. After adding 4N hydrogen chloride in EtOAc (10ml) to the solution, the resulting precipitate was collected byfiltration, washed with EtOAc and dried in vacuo to give3-(3-bromopropyl)aniline hydrochloride (2.32 g).

¹H-NMR (DMSO-d₆) δ: 1.95-2.20(2H, m), 2.5-2.8(2H, m), 3.52(2H, t, J=6.6Hz), 7.15-7.30(2H, m), 7.35-7.50(1H, m).

Mass: 214.2, 216.1(M+H)+.

REFERENCE EXAMPLE 21

Oxalyl chloride (1.14 g) was added dropwise to a solution of1,4-dioxaspiro[4,5]decane-6-carboxylic acid (559 mg) and DMF (1 drop) inDCM (5 ml), and the mixture was stirred for 2 hours at room temperature.After removing the solvent under reduced pressure, the residue wasdissolved in DCM (5 ml). The solution was added dropwise to a solutionof 3-(3-bromopropyl)aniline hydrochloride (752 mg) and triethylamine(1.67 ml) in DCM (10 ml). The solution was stirred for 2 hours at roomtemperature and poured into a mixture of water and DCM. The separatedorganic layer was washed with 1N aqueous hydrogen chloride, water, anaqueous saturated sodium hydrogencarbonate solution and brine,successively and dried over magnesium sulfate. After evaporation of thesolvent, the residue was purified by column chromatography on silica-geleluting with a mixture of DCM and acetone to give

N-[3-(3-bromopropyl)phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide(1.07 g).

¹H-NMR (DMSO-d₆) δ: 1.2-2.2(10H, m), 2.6-2.7(3H, m), 3.51(2H, t, J=6.6Hz), 3.75-3.90(4H, m), 6.87(1H, d, J=7.7 Hz), 7.19(1H, t, J=7.7 Hz),7.41(1H, d, J=7.7 Hz), 7.48(1H, s), 9.57(1H, s).

Mass: 380.1, 382.2(M-H)−

REFERENCE EXAMPLE 22

The following compounds (1) to (4) were obtained in a similar manner toReference Example 21.

(1)

N-[3-(2-Bromoethyl)phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide

¹H-NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.7(1H, m), 3.08(2H, t, J=7.1Hz), 3.70(2H, t, J=7.1 Hz), 3.7-3.9(4H, m), 6.94(1H, d, J=7.6 Hz),7.21(1H, t, J=7.6 Hz), 7.45(1H, d, J=7.6 Hz), 7.50(1H, s), 9.59(1H, s).

Mass: 390.1, 392.1 (M+Na)+.

(2)

N-(3-Bromophenyl)-1,4-dioxaspiro[4.5]decane-6-carboxamide ¹H-NMR(DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.7(1H, m), 3.7-3.9(4H, m),7.15-7.30(2H, m), 7.4-7.5(1H, m), 7.99(1H, s), 9.83(1H, s).

Mass: 338.1, 340.1 (M-H)−.

(3)

N-[3-(Methylthio)phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide ¹H-NMR(DMSO-d₆) δ: 1.2-1.95(6H, m), 2.44(3H, s), 2.6-2.65(1H, m),3.75-3.90(4H, m), 6.85-6.95(1H, m), 7.21(1H, t, J=7.9 Hz), 7.31(1H, d,J=7.9 Hz), 7.60(1H, s), 9.66(1H, s).

Mass: 330.3(M+Na)+.

(4)

N-(2-Methoxyphenyl)-1,4-dioxaspiro[4.5]decane-6-carboxamide ¹H-NMR(DMSO-d₆) δ: 1.25-1.8(6H, m), 1.85-1.95(2H, m), 2.70-2.75(1H, m),3.86(3H, s), 3.9-4.0(4H, m), 6.85-7.05(4H, m), 8.16(1H, d, J=7.6 Hz),9.15(1H, s).

Mass: 314.3(M+Na)+.

REFERENCE EXAMPLE 23

60% Perchloric acid (1.35 g) was added to a solution ofN-[3-(3-bromopropyl)phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide(1.03 g) in DCM (10 ml) at room temperature and the mixture was stirredfor 10 minutes. The solution was carefully poured into an aqueoussaturated sodium hydrogencarbonate solution and the mixture was stirredfor 30 minutes. The organic layer was separated and the aqueous layerwas extracted with chloroform. The combined organic layer was dried overmagnesium sulfate. After evaporation of the solvent, the residue wasdissolved in 90% aqueous sulfonic acid. The solution was heated at 60°C. for 20 minutes and then poured on ice. The solution was stirred for30 minutes. The resulting precipitate was collected by filtration,washed successfully with water and dried in vacuo to give3-(3-bromopropyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (580 mg).

¹H-NMR (DMSO-d₆) δ: 1.60-1.75(4H, m), 2.0-2.2(2H, m), 2.4-2.5(2H, m),2.7-2.8(2H, m), 3.52(2H, t, J=6.6 Hz), 7.04(1H, d, J=8.3 Hz), 7.10(1H,s), 7.59(1H, d, J=8.3 Hz), 11.52(1H, s).

Mass: 318.2, 320.1 (M+H)+

REFERENCE EXAMPLE 24

The following compounds (1) to (5) were obtained in a similar manner toReference Example 23.

(1)

3-(2-Bromoethyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone 1H-NMR(DMSO-d₆) δ: 1.6-1.9(4H, m), 2.45-2.55(2H, m), 2.75-2.90(2H, m),3.17(2H, t, J=7.1 Hz), 3.74(2H, t, J=7.1 Hz), 7.10(1H, d, J=8.2 Hz),7.12(1H, s), 7.62(1H, d, J=8.2 Hz).

Mass: 328.2, 330.1(M+Na)+.

(2)

3-Bromo-7,8,9,10-tetrahydro-6 (5H)-phenanthridinone ¹H-NMR (DMSO-d₆) δ:1.6-1.75(4H, m), 2.4-2.5(2H, m), 2.7-2.8(2H, m), 7.32(1H, dd, J=8.6, 1.9Hz), 7.45(1H, d, J=1.9 Hz), 7.61(1H, d, J=8.6 Hz), 11.67(1H, s).

Mass: 300.1, 302.1(M+Na)+.

(3)

3-(Methylthio)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone ¹H-NMR(DMSO-d₆) δ: 1.65-1.85(4H, m), 2.4-2.5(2H, m), 2.75-2.85(2H, m),3.45(3H, s), 7.05(1H, d, J=8.3 Hz), 7.11(1H, s), 7.58(1H, d, J=8.3 Hz),11.48(1H, s).

Mass: 258.2(M+Na)+.

(4)

4-Methoxy-7,8,9,10-tetrahydro-6(5H)-phenanthridinone ¹H-NMR (DMSO-d₆) δ:1.65-1.85(4H, m), 2.4-2.5(2H, m), 2.75-2.85(2H, m), 3.89(3H, s),7.05-7.15(2H, m), 7.25-7.30(1H, m), 10.51(1H, s).

Mass: 252.3(M+Na)+.

(5)

3-(Bromomethyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone ¹H-NMR(DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.55(2H, m), 2.75-2.9(2H, m), 3.56(2H,s), 7.23(1H, dd, J=8.3, 1.6 Hz), 7.32(1H, d, J=1.6 Hz), 7.66(1H, d,J=8.3 Hz), 11.67(1H, s).

Mass: 314.1, 316.0 (M+Na)+.

REFERENCE EXAMPLE 25

A suspension of3-(methylthio)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (180 mg) inDMF (18 ml) was heated at 90° C. to solve the compound. OXONE®(monopersulfate compound, 2KHSO₅·KHSO₄·K₂SO₄, produced by Du Pont) (902mg) in water (3 ml) was added to this solution. The mixture was stirredfor 30 minutes at the same temperature and stirred overnight at roomtemperature. The mixture was poured into a mixture of water and EtOAc.The separated organic layer was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the residue wasrecrystallized in MeOH. The crystalline was collected by filtration,washed with MeOH and dried under reduced pressure to give3-(methylsulfonyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (112 mg).

IR (KBr) cm⁻¹: 2931, 1660, 1641, 1560.

¹H-NMR (DMSO-d₆) δ: 1.65-1.85(4H, m), 2.45-2.55(2H, m), 2.8-2.9(2H, m),3.24(3H, s), 7.66(1H, dd, J=8.5, 1.8 Hz), 7.82(1H, d, J=1.8 Hz),7.91(1H, d, J=8.5 Hz), 11.95(1H, s).

REFERENCE EXAMPLE 26

Under a nitrogen atmosphere, 1M DCM solution of boron tribromide (4.4ml) was added to a solution of4-methoxy-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (252 mg) in DCM (10ml) at 0° C. The mixture was stirred for 2 hours and poured into amixture of water and EtOAc. The separated organic layer was washed withbrine and dried over magnesium sulfate. After evaporation of thesolvent, the crude product was recrystallized in MeOH. The crystallinewas collected by filtration, washed with MeOH and dried under reducedpressure to give 4-hydroxy-7,8,9,10-tetrahydro-6(5H)-phenanthridinone(151 mg).

IR (KBr) cm⁻¹: 1644, 1602, 1563.

¹H-NMR (DMSO-d₆) δ: 1.6-1.85(4H, m), 2.35-2.45(2H, m), 2.7-2.9(2H, m),6.91(1H, dd, J=7.6, 1.2 Hz), 6.99(1H, t, J=7.6 Hz), 7.14(1H, dd, J=7.6,1.2 Hz), 10.15(1H, s).

Mass: 238.2(M+Na)+.

REFERENCE EXAMPLE 27

To a solution of 1,4-dioxaspiro[4,5]decane-6-carboxylic acid (1.87 g)and 3-aminobenzylalcohol (1.24 g) in DCM (100 ml) were addedsuccessively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(2.89 g) and N,N-dimethylaminopyridine (613 mg). The mixture was stirredovernight at room temperature and poured into a mixture of water andDCM. The separated organic layer was washed with a diluted aqueoushydrogen chloride solution and brine, successively and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography on silica-gel eluting with a mixtureof DCM and acetone to giveN-[3-(hydroxymethyl)phenyl)-1,4-dioxaspiro[4.5]decane-6-carboxamide(1.61 g).

1H-NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.7(1H, m), 3.7-4.0(4H, m),4.44(2H, d, J=5.7 Hz), 5.16(1H, t, J=5.7 Hz), 6.95(1H, d, J=7.8 Hz),7.20(1H, t, J=7.8 Hz), 7.44(1H, d, J=7.8 Hz), 7.58(1H, s), 9.60(1H, s).

REFERENCE EXAMPLE 28

Oxaryl chloride (3.82 g) and 1 drop of DMF were added successively to asolution of 1,4-dioxaspiro[4,5]decane-6-carboxylic acid (1.87 g) in DCM(15 ml) at room temperature. The solution was stirred for 2 hours atroom temperature and the solvent was evaporated. The residue was dilutedwith DCM (5 ml) and added dropwise to a mixture of 3-nitroaniline (1.39g) and triethylamine (3.05 g) in DCM (8.5 ml) under ice cooling. After10 minutes the ice bath was removed and the mixture was stirred at roomtemperature for 1.5 hours and poured into a mixture of water and EtOAc.The organic phase was separated and washed with diluted aqueous hydrogenchloride, brine and then dried over magnesium sulfate. After evaporationof the solvent, the residue was purified by column chromatography onsilica-gel eluting with DCM-acetone to affordN-(3-nitrophenyl)-1,4-dioxaspiro[4.5]decane-6-carboxamide (1.6 g).

¹H NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.75(1H, m), 3.7-3.95(4H, m),7.58(1H, t, J=8.1 Hz), 7.8-8.0(2H, m), 8.68(1H, t, J=2.1 Hz), 10.20(1H,s).

Mass (APCI) m/e:329.2(M+Na)+.

REFERENCE EXAMPLE 29

10% Palladium on carbon (50% wet, 160 mg) was added to a solution ofN-(3-nitrophenyl)-1,4-dioxaspiro[4,5]decane-6-carboxamide (1.6 g) inMeOH (20 ml). The mixture was hydrogenated under hydrogen atmosphere atatmospheric pressure for 6 hours. Unsoluble material was removed byfiltration through celite. The filtrate was concentrated in vacuo toafford N-(3-aminophenyl)-1,4-dioxaspiro[4,5]decane-6-carboxamide (1.24g). ¹H NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.63(1H, dd, J=11.1, 4.6 Hz),3.9-4.05(4H, m), 6.35-6.45(1H, m), 6.43(1H, dd, J=7.8, 1.5 Hz), 7.05(1H,t, J=7.8 Hz), 7.2-7.3(1H, m), 8.22(1H, s).

Mass (APCI) m/e: 299.3(M+Na)+.

REFERENCE EXAMPLE 30

N-(3-aminophenyl)-1,4-dioxaspiro[4,5]decane-6-carboxamide (930 mg) wasdissolved in chloroform (15 ml), and phthalic anhydride (499 mg) wasadded to the solution. The mixture was stirred under reflux for 4 hoursand cooled to room temperature. The solvent was evaporated in vacuo andthe resulting residue was purified by column chromatography onsilica-gel eluting with hexane-EtOAc to affordN-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-1,4-dioxaspiro-[4,5]decane-6-carboxamide (800 mg).

¹H NMR (DMSO-d₆) δ: 1.1-2.0(8H, m), 2.6-2.7(1H, m), 3.75-3.95(4H, m),7.10(1H, dd, J=8.0, 1.8 Hz), 7.42(1H, t, J=8.0 Hz), 7.61(1H, d, J=8.0Hz), 7.77(1H, t, J=1.8 Hz), 7.85-8.0(4H, m), 9.89(1H, s).

Mass (APCI) m/e: 429.2(M+Na)+.

REFERENCE EXAMPLE 31

N-[3-(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-phenyl]-1,4-dioxaspiro[4,5]decane-6-carboxamidewas obtained in a similar manner to Reference Example 30.

¹H NMR (DMSO-d₆) δ: 1.2-2.0(8H, m), 2.6-2.8(1H, m), 3.75-4.0(4H, m),7.12(1H, d, J=8.0 Hz), 7.43(1H, t, J=8.0 Hz), 7.45-8.0(4H, m), 9.89(1H,s).

REFERENCE EXAMPLE 32

60% Perchloric acid (1.06 g) was added to a solution ofN-13-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-1,4-dioxaspiro-[4,5]decane-6-carboxamide(860 mg) in DCM (50 ml) at room temperature and stirred for 10 minutes.The solution was carefully poured into saturated aqueous solution ofsodium hydrogencarbonate and stirred for 30 minutes. The organic layerwas dried over magnesium sulfate. After evaporation of the solvents, theresidue was dissolved in 90% sulfuric acid. The solution was heated at60° C. for 20 minutes and poured on ice. The solution was stirred for 30minutes and the resulting precipitates were collected by filtration,washed with water and dried in vacuo to afford2-(6-oxo-5,6,7,8,9,10-hexahydro-3-phenanthridinyl)-1H-isoindol-1,3(2H)-dione(480 mg).

¹H NMR (DMSO-d₆) δ: 1.6-1.8(6H, m), 2.8-3.0(2H, m), 7.28(1H, dd, J=8.7,1.9 Hz), 7.40(1H, d, J=1.9 Hz), 7.81(1H, d, J=8.7 Hz), 7.85-8.0(4H, m),11.80(1H, s).

Mass (APCI m/e: 367.2(M+Na)+.

REFERENCE EXAMPLE 33

Hydrazine monohydrate (209 mg) was added to a solution of2-(6-oxo-5,6,7,8,9,10-hexahydro-3-phenanthridinyl)-3a,7a-dihydro-1H-isoindol-1,3(2H)-dione(480 mg) in THF (20 ml). The mixture was stirred under reflux for 9hours and cooled to room temperature. The solvent was evaporated invacuo and the residue was purified by column chromatography onsilica-gel eluting with DCM-acetone to afford3-amino-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (280 mg).

¹H NMR (DMSO-d₆) δ: 1.7-1.9(4H, m), 2.3-2.45(2H, m), 2.6-2.8(2H, m),5.5(2H, br s), 6.36(1H, d, J=2.1 Hz), 6.44(1H, dd, J=8.6, 2.1 Hz),7.31(1H, d, J=8.6 Hz), 11.16(1H, s).

Mass (APCI) m/e: 237.3(M+Na)+.

REFERENCE EXAMPLE 34

Copper (1.95 g) was added to a mixture of methyl 2-iodobenzoate (7.0 g)and 4-bromo-3-nitrobenzoic acid methylester (6.95 g). The whole mixturewas stirred at 200° C. for 5 hours. The mixture was cooled to roomtemperature and diluted with a mixture of EtOAc and water. Copper wasremoved by filtration, and the organic phase was separated, washed withwater and brine and then dried over magnesium sulfate. After evaporationof the solvent the residue was purified by column chromatography onsilica-gel eluting with hexane-EtOAc to afford dimethyl2′-nitro-1,1′-biphenyl-2,4′-dicarboxylate (3.5 g).

¹H NMR (DMSO-d₆) δ: 3.59(3H, s), 3.95(3H, s), 7.37(1H, dd, J=7.6, 1.3Hz), 7.5-7.8(3H, m), 8.03(1H, dd, J=7.7, 1.2 Hz), 8.27(1H, dd, J=8.0,1.6 Hz), 8.57(1H, d, J=1.6 Hz).

Mass (APCI) m/e :338.3(M+Na)+.

REFERENCE EXAMPLE 35

Dimethyl 2′-nitro-1′,1-biphenyl-2,4′-dicarboxylate (2.0 g) was dissolvedin a mixture of THF (30 ml), ethanol (60 ml) and water (9 ml). To thissolution were added ammonium chloride (20 mg) and iron (200 mg) and themixture was refluxed for 5 hours. The solution was cooled to roomtemperature and 4N aqueous sodium hydroxide (8 ml) and water (8 ml) wereadded. The whole mixture was stirred for 16 hours at room temperature.Unsoluble material was removed by filtration and the filtrate wasconcentrated in vacuo. The filtrate was diluted with water and washedwith EtOAc. The aqueous phase was acidified with conc. HCl and resultingprecipitates were collected by filtration, washed with EtOAc and driedin vacuo to afford 6-oxo-5,6-dihydro-3-phenanthridine-carboxylic acid(710 mg).

¹H NMR (DMSO-d₆) δ: 7.65-7.80(2H, m), 7.86(1H, dt, J=12.2, 1.4 Hz),8.00(1H, d, J=1.5 Hz), 8.35(1H, dd, J=7.9, 1.2 Hz), 8.45-8.60(2H, m),11.87(1H, s).

REFERENCE EXAMPLE 36

Under ice cooling, isobutyl chloroformate (497 mg) was added dropwise toa mixture of 6-oxo-5,6-dihydro-3-phenanthridinecarboxylic acid (725 mg)and triethylamine (613 mg) in THF (20 ml). The mixture was stirred for1.5 hours at the same temperature. In another vessel sodium borohydride(459 mg) was dissolved in a mire of THF (10 ml) and water (20 ml) andcooled with ice. To this solution was added the above mixture over 10minutes The mixture was stirred for 1.5 hours under ice cooling andpoured into a mixture of water and EtOAc. The organic phase wasseparated and washed with water and brine, and then dried over magnesiumsulfate. After evaporation of the solvent the residue was purified bycolumn chromatography on silica-gel eluting with DCM-acetone to afford3-(hydroxymethyl)-6(5H)-phenanthridinone (410 mg).

¹H NMR (DMSO-d₆) δ: 4.60(2H, d, J=5.6 Hz), 5.36(1H, t, J=5.6 Hz),7.20(1H, dd, J=8.3, 0.9 Hz), 7.36(1H, s), 7.62(1H, t, J=7.4 Hz),7.84(1H, t, J=8.3 Hz), 8.3-8.35(2H, m), 8.47(1H, d, J=8.1 Hz), 11.68(1H,s).

Mass (APCI) m/e:248.3(M+Na)+.

REFERENCE EXAMPLE 37

3-(hydroymethyl)-6(5H)-phenanthridinone (370 mg) was suspended inphosphorus oxychloride (4 ml) and the mixture was stirred under refluxfor 3.5 hours. The clear solution was poured into a mixture of water andchloroform and neutralized with saturated aqueous sodium hydrogencarbonate. The mixture was stirred for 30 minutes while the solution pHwas maintained between 7 and 9. The organic phase was separated andwashed with water and brine, and then dried over magnesium sulfate.After evaporation of the solvent the residue was purified by columnchromatography on silica-gel eluting with DCM to afford6-chloro-3-(chloromethyl)phenanthridine (256 mg).

¹H NMR (DMSO-d₆) δ: :5.03(2H, s), 7.8-8.15(4H, m), 8.45(1H, dd, J=8.2,1.0 Hz), 8.86(1H, d, J=8.5 Hz), 8.93(1H, d, J=8.2 Hz).

Mass (APCI) m/e: 284.1, 286.1(M+Na)+.

EXAMPLE 1

50% Pd/C catalyst (50% wet, 10 mg) was added to a solution of2-{3-[4-phenyl-3,6-dihydro-1(2H)-pyridyl]propyl}-6(5H)-phenanthridinone(85 mg) in a mixture of THF (5 ml) and MeOH (5 ml). The mixture wasstirred under hydrogen at atmospheric pressure until hydrogen gasabsorption stopped. After filtration through celite and removal of thesolvent, the residue was purified by column chromatography on silica-geleluting with a mixture of chloroform and MeOH to give2-[3-(4-phenylpiperidin-1-yl)propyl]-6(5H)-phenanthridinone (65 mg).

IR (KBr) cm⁻¹: 1666, 1608.

¹H-NMR (DMSO-d₆) δ: 1.6-2.1(8H, m), 2.2-2.5(3H, m), 2.72(2H, t, J=7.2Hz), 2.98(2H, d, J=11.2 Hz), 7.1-7.4(7H, m), 7.63(1H, t, J=7.3 Hz),7.84(1H, t, J=7.3 Hz), 8.23(1H, s), 8.32(1H, d, J=8.0 Hz), 8.54(1H, d,J=8.0 Hz).

Mass: 397.4 (M+H)+.

EXAMPLE 2

4-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (152 mg) wasadded to a solution of 2-(3-bromopropyl)-6(5H)-phenanthridinone (150 mg)in DMF (3 ml) at room temperature. Triethylamine (0.66 ml) was added tothe mixture cooled in an ice bath. The whole mixture was stirred for 1hour in the ice bath and stirred overnight at ambient temperature. Themixture was poured into a mixture of water and EtOAc. The separatedorganic layer was washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue was purified by columnchromatography on silica-gel eluting with a mixture of DCM and acetoneand then a mixture of chloroform and MeOH to give2-{3-[4-(4-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]propyl}-6(5H)-phenanthridinone (78 mg).

¹H-NMR (DMSO-d₆) δ: 1.75-2.0(2H, m), 2.3-2.9(6H, m), 3.06(2H, s),6.12(1H, s), 7.1-7.5(6H, m), 7.63(1H, t, J=7.6 Hz), 7.84(1H, t, J=7.0Hz), 8.23(1H, s), 8.32(1H, d, J=7.5 Hz), 8.52(1H, d, J=8.0 Hz),11.62(1H, s).

Mass: 413.13 (M+H)+.

The compounds in the following Examples 3 to 21 were obtained in asimilar manner to Example 2.

EXAMPLE 3

2-{3-[4-Phenyl-3,6-dihydro-1(2H)-pyridyl]propyl}-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.8-2.0(2H, m), 2.4-2.5(4H, m), 2.6-2.8(4H, m),3.08(2H, d, J=2.8 Hz), 6.15(1H, s), 7.1-7.5(7H, m), 7.63(1H, t, J=7.2Hz), 7.84(1H, t, J=7.2 Hz), 8.23(1H, s), 8.32(1H, d, J=8.0 Hz), 8.53(1H,d, J=8.0 Hz), 11.61 (1H, s).

Mass: 395.3 (M+H)+.

EXAMPLE 4

2-{3-[4-(4-Chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]propyl}-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.8-2.0(2H, m), 2.45-2.8(8H, m), 3.09(2H, m),6.20(2H, m), 7.25-7.50(6H, m), 7.62(1H, t, J=7.1 Hz), 7.84(1H, t, J=7.1Hz), 8.23(1H, s), 8.31(1H, d, J=7.9 Hz), 8.52(1H, d, J=8.0 Hz),11.60(1H, s).

Mass: 429.2 (M+H)+.

EXAMPLE 5

2-{3-[4-(4-Methoxyphenyl)-3,6-dihydro-1(2H)-pyridyl]propyl}-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.75-2.0(2H, m), 2.3-2.9(8H, m), 3.06(2H, s),3.74(3H, s), 6.03(1H, s), 6.88(2H, d, J=8.6 Hz), 7.25-7.40(4H, m),7.63(1H, t, J=7.5 Hz), 7.84(1H, t, J=7.0 Hz), 8.23(1H, s), 8.32(1H, d,J=7.7 Hz), 8.53(1H, d, J=8.1 Hz), 11.61(1H, s).

Mass: 425.0 (M+H)+.

EXAMPLE 6

2-{3-[4-(4-Cyanophenyl)-1-piperazinyl]propyl}-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.8-2.0(2H, m), 2.2-2.4(2H, m), 2.4-2.6(8H, m),2.73(2H, t, J=7.0 Hz), 6.95-7.05(2H, m), 7.25-7.40(2H, m), 7.5-7.65(3H,m), 7.84(1H, t, J=7.0 Hz), 8.22(1H, s), 8.25-8.35(1H, m), 8.52(1H, d,J=8.0 Hz), 11.60(1H, s).

Mass: 423.3 (M+H)+.

EXAMPLE 7

8-Chloro-2-{3-[4-(4-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-propyl}-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.75-2.0(2H, m), 2.3-2.8(8H, m), 3.07(2H, s),6.11(1H, s), 7.0-7.5(6H, m), 7.87(1H, dd, J=8.6, 2.0 Hz), 8.0-8.4(2H,m), 8.57(1H, d, J=8.0 Hz), 11.78(1H, s).

Mass: 447.3 (M+H)+.

EXAMPLE 8

8-Chloro-2-{3-[4-[4-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]propyl}6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.8-2.0(2H, m), 2.4-2.8(8H, m), 3.12(2H, d, J=2.7Hz), 6.34(1H, s), 7.2-7.4(2H, m), 7.5-7.7(5H, m), 7.84(1H, dt, J=7.2,1.5 Hz), 8.23(1H, s), 8.25-8.35(1H, m), 8.53(1H, d, J=8.2 Hz), 11.60(1H,s).

Mass: 463.4 (M+H)+.

EXAMPLE 9

8-Chloro-2-[3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]-indol-2-yl)propyl]-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.85-2.1(2H, m), 2.4-2.9(8H, m), 3.58(3H, s),6.35(2H, s), 6.9-7.2(2H, m), 7.25-7.5(4H, m), 7.8-8.0(1H, m),8.2-8.4(2H, m), 8.55(1H, d, J=8.8 Hz), 11.78(1H, s).

Mass: 456.0, 458.0 (M⁺).

EXAMPLE 10

2-[4-(4-Phenyl-3,6-dihydro-1(2H)-pyridyl)butyl]-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.45-1.8(4H, m), 2.35-2.8(8H, m), 3.03(2H, d, J=2.0Hz), 6.12(1H, s), 7.2-7.45(7H, m), 7.55-7.7(1H, m), 7.8-7.9(1H, m),8.21(1H, s), 8.25-8.35(1H, m), 8.52(1H, d, J=8.2 Hz), 11.60(1H, s).

Mass: 409.4 (M+H)+.

EXAMPLE 11

2-[2-(4-Phenyl-3,6-dihydro-1(2H)-pyridyl)ethoxy]-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.55(2H, m), 2.65-2.95(8H, m),3.15-3.30(2H, m), 4.18(2H, t, J=5.8 Hz), 6.16(1H, s), 7.0-7.7(8H, m),11.47(1H, s).

Mass: 401.3 (M+H)+.

EXAMPLE 12

2-{2-[4-(4-Chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]ethoxy}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.55(2H, m), 2.6-3.0(8H, m),3.2-3.4(2H, m), 4.15-4.30(2H, m), 6.15(1H, s), 7.1-7.7(7H, m), 11.49(1H,s).

Mass 435.3 (M+H)⁺.

EXAMPLE 13

3-{2-[4-(4-Chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]propyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.65-1.90(6H, m), 2.3-2.9(10H, m), 3.05(2H, s),3.3(2H, s), 6.19(1H, s), 7.05(1H, d, J=8.9 Hz), 7.10(1H, s), 7.36(2H, d,J=8.7 Hz), 7.46(2H, d, J=8.7 Hz), 7.70(2H, d, J=8.9 Hz), 11.50(1H, s).

Mass: 433.4 (M+H)+.

EXAMPLE 14

3-{2-[4-(4-Chlorophenyl)-1-piperazinyl]propyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(6H, m), 2.25-2.9(12H, m), 3.05-3.2(4H, m),6.83(2H, d, J=8.9 Hz), 6.93(1H, d, J=8.2 Hz), 7.02(1H, s), 7.21(2H, d,J=8.9 Hz), 7.58(1H, d, J=8.2 Hz), 11.50(1H, s).

Mass: 435.99 (M+H)+.

EXAMPLE 15

3-{[4-(4-Chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.3-2.5(2H, m), 2.65-2.9(4H, m),3.06(2H, s), 3.4-3.5(2H, m), 3.63(2H, s), 6.19(1H, s), 7.1-7.7(7H, m),11.53(1H, s).

Mass: 405.3(M+H)+.

EXAMPLE 16

3-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.3-2.5(2H, m), 2.65-2.9(4H, m),3.06(2H, s), 3.4-3.5(2H, m), 3.63(2H, s), 6.19(1H, s), 7.1-7.7(7H, m),11.53(1H, s).

Mass: 405.3(M+H)+.

EXAMPLE 17

3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)-6(5H)-phenanthridinone

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.6(2H, m), 2.7-2.9(2H, m),4.02(2H, d, J=8.5 Hz), 4.22(2H, d, J=8.5 Hz), 4.41(2H, s), 5.75(1H, d,J=2.6 Hz), 7.17(1H, d, J=8.0 Hz), 7.30(1H, s), 7.68(1H, d, J=8.0 Hz),7.96(1H, d, J=2.6 Hz).

Mass (APCI) m/e: 321.2 (M+H)+.

EXAMPLE 18

2-[(6-oxo-5,6,7,8,9,10-hexahydro-3-phenanthridinyl)-methyl]-1H-isoindol-1,3(2H)-dione

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.5-2.6(2H, m), 2.7-2.9(2H, m),4.82(2H, s), 7.12(1H, dd, J=8.3, 1.5 Hz), 7.21(1H, d, J=1.5 Hz),7.63(1H, dd, J=8.3 Hz), 7.8-8.0(4H, m), 11.47(1H, s).

Mass (APCI) m/e: 381.1(M+Na)+.

EXAMPLE 19

3-[(9-methyl-1,3,4,9-tetrahydro-2H-beta-carbolin-2-yl)-methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.6(2H, m), 2.7-3.0(4H, m),3.5-3.7(4H, m), 3.54(3H, s), 3.82(2H, s), 6.9-7.4(6H, m), 7.65(1H, d,J=8.2 Hz), 11.57(1H, s).

Mass (APCI) m/e: 398.3(M+H)+.

EXAMPLE 20

3-{[4-(5-methyl-2-pyridyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H NMR (DMSO-d₆) δ: 1.6-1.9(8H, m), 2.0-2.2(4H, m), 2.24(3H, s),2.4-3.0(7H, m), 3.55(2H, s), 7.14(1H, d, J=7.9 Hz), 7.15(1H, d, J=7.9Hz), 7.26(1H, d, J=2.1 Hz), 7.50(1H, dd, J=8.2,2.1 Hz), 7.62(1H, d,J=8.2 Hz), 8.31(1H, s), 11.54(1H, s).

Mass (APCI) m/e: 388.3(M+H)+.

EXAMPLE 21

3-{[4-[4-(trifluoromethoxy)phenyl]-3,6-dihydro-1(2H)-pyridyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinone

¹H NMR (DMSO-d₆) δ: 1.6-1.9(6H, m), 2.3-2.5(2H, m), 2.55-2.75(2H, m),2.75-2.9(2H, m), 3.0-3.15(2H, m), 3.63(2H, s), 6.20(1H, s), 7.15(1H, d,J=8.2 Hz), 7.29(1H, s), 7.31(2H, d, J=8.8 Hz), 7.54(2H, d, J=8.8 Hz),7.63(1H, d, J=8.2 Hz), 11.55(1H, s).

Mass (APCI) m/e: 455.1(M+H)+.

EXAMPLE 22

4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (225 mg) andtriethylamine (0.91 ml) were added successively to a solution of3-(2-bromoethyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (200 mg) inDMF (4 ml) at room temperature. The whole mixture was stirred overnightat ambient temperature. The mixture was poured into a mixture of waterand EtOAc. The separated organic layer was washed with brine and driedover magnesium sulfate. After evaporation of the solvent, the residuewas purified by column chromatography on silica-gel eluting with amixture of DCM and acetone and then a mixture of chloroform and MeOH. Asuspension of the product in MeOH (2 ml) was added with 4N hydrogenchloride (0.5 ml) to dissolve. The crystalline of the product wasemerged after 1 hour. The crystalline product was collected byfiltration, washed with MeOH and dried under reduced pressure to give3-{2-[4-(4-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]ethyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride (133 mg). ¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m),2.45-2.55(2H, m), 2.7-2.95 (2H, m), 6.27(1H, s), 7.13(1H, d, J=8.1 Hz),7.16(1H, s), 7.45(2H, d, J=8.7 Hz), 7.55(2H, d, J=8.7 Hz), 7.67(1H, d,J=8.1 Hz), 10.69(1H, br s), 11.65(1H, s), 3.1-4.2(10H, m).

Mass: 419.2(M+Na)⁺.

The compounds in the following Examples 23 to 39 were obtained in asimilar manner to Example 22.

EXAMPLE 23

3-{2-[4-(4-Chlorophenyl)-1-piperazinyl]ethyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonedihydrochloride

¹H-NMR (DMSO-d₆) δ: 1.65-1.85(4H, m), 2.45-2.55(2H, m), 2.75-2.85(2H,m), 3.15-3.25(8H, m), 3.6-3.7(2H, m), 3.8-3.9(2H, m), 7.03(2H, d, J=9.0Hz), 7.10(1H, d, J=8.4 Hz), 7.15(1H, s), 7.29(1H, d, J=8.4 Hz), 7.66(1H,d, J=8.4 Hz), 11.17(1H, br s), 11.65(1H, s).

Mass: 422.2 (M+H)+.

EXAMPLE 24

3-[3-(4-Morpholinyl)propyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

IR (KBr) cm⁻¹: 3276, 1625, 1567.

¹H-NMR (DMSO-d₆) δ: 1.65-1.85(4H, m), 2.0-2.15(2H, m), 2.4-2.5(2H, m),2.65-2.85(4H, m), 2.95-3.15(4H, m), 3.35-3.45(2H, m), 3.8-4.0(4H, m),7.06(1H, dd, J=8.3, 1.6 Hz), 7.12(1H, d, J=1.6 Hz), 7.61(1H, d, J=8.3Hz).

Mass: 327.3(M+H)+.

EXAMPLE 25

3- [(4-Morpholinyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

IR (KBr) cm⁻¹: 3436, 1643, 1560.

¹H-NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.46(2H, s), 2.82(2H, s),3.1-3.4(4H, m), 3.8-4.0(4H, m), 4.38(2H, s), 7.40(1H, s), 7.55(1H, d,J=8.0 Hz), 7.74(1H, d, J=8.0 Hz), 11.54(1H, s), 11.85(1H, s).

Mass: 299.3(M+H)+.

EXAMPLE 26

3-{[4-Phenyl-3,6-dihydro-1(2H)-pyridyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H-NMR (DMSO-d₆) δ: 1.65-1.90(4H, m), 2.45-2.55(2H, m), 2.7-2.9(4H, m),3.5-3.9(4H, m), 4.48(2H, m), 6.16(1H, s), 7.25-7.55(7H, m), 7.78(1H, d,J=8.2 Hz), 10.78(1H, br s), 11.86(1H, s).

Mass: 371.4 (M+H)+.

EXAMPLE 27

3-[(4-Phenylpiperidin-1-yl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H-NMR (DMSO-d₆) δ: 1.6-2.2(10H, m), 2.7-2.9(4H, m), 3.0-3.2(2H, m),3.3-3.4(1H, m), 4.37(2H, d, J=4.8 Hz), 7.15-7.45(6H, m), 7.52(1H, d,J=8.2 Hz), 7.77(1H, d, J=8.2 Hz), 10.76(1H, br s), 11.84(1H, s).

Mass: 373.4 (M+H)+.

EXAMPLE 28

3-{[4-(4-fluorophenyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δd: 1.6-2.2(8H, m), 2.3-2.55(2H, m), 2.7-3.2(5H, m),3.3-3.5(2H, m), 4.37(2H, d, J=4.8 Hz), 7.1-7.3(4H, m), 7.40(1H, s),7.56(1H, d, J=8.3 Hz), 7.76(1H, d, J=8.3 Hz), 11.04(1H, br s), 11.85(1H,s).

Mass (APCI) m/e: 391.4(M+H)+.

EXAMPLE 29

3-{[4-(4-methoxyphenyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-2.2(8H, m), 2.6-3.2(5H, m), 3.2-3.5(2H, m),3.5-3.8(2H, m), 4.36(2H, d, J=4.5 Hz), 6.88(2H, d, J=8.6 Hz), 7.13(2H,d, J=8.6 Hz), 7.33(1H, s), 7.55(1H, d, J=8.3 Hz), 7.76(1H, d, J=8.3 Hz),10.94(1H, br s), 11.85(1H, s).

Mass (APCI) m/e: 403.4 (M+H)+.

EXAMPLE 30

3-{[4-(4-methylphenyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-2.2(8H, m), 2.4-2.6(2H, m), 2.25(3H, s),2.6-3.3(5H, m), 3.4-3.6(2H, m), 4.36(2H, d, J=4.7 Hz), 7.06(4H, s),7.40(1H, s), 7.57(2H, d, J=8.3 Hz), 7.75(2H, d, J=8.3 Hz), 11.07(1H, brs), 11.85(1H, s).

Mass (APCI) m/e: 387.4(M+H)⁺.

EXAMPLE 31

3-{14-(4-chlorophenyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-2.2(8H, m), 2.3-2.5(2H, m), 2.7-3.2(5H, m),3.3-3.5(2H, m), 4.37(2H, s), 7.2-7.6(6H, m), 7.75(1H, d, J=8.2 Hz),10.95(1H, br s), 11.85(1H, s).

Mass (APCI) m/e: 407.3(M+H)+.

EXAMPLE 32

3-({4-[4-(trifluoromethyl)phenyl]-1-piperidyl}methyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-2.4(8H, m), 2.3-2.5(2H, m), 2.7-3.3(3H, m),3.4-3.75(4H, m), 4.39(2H, d, J=4.6 Hz), 7.4-7.5(3H, m), 7.56(1H, d,J=8.3 Hz), 7.6-7.8(3H, m), 11.05(1H, br s), 11.86(1H, s).

Mass (APCI) m/e: 441.3 (M+H)+.

EXAMPLE 33

3-{[4-(2-pyridyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonedihydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.1-2.6(6H, m), 2.8-3.6(7H, m),4.40(2H, d, J=4.1 Hz), 7.34(1H, s), 7.4-8.0(4H, m), 8.51(1H, t, J=7.8Hz), 8.80(1H, d, J=5.7 Hz), 11.39(1H, br s), 11.86(1H, s).

Mass (APCI) m/e: 374.4 (M+H)+.

EXAMPLE 34

3-[(4-benzyl-1-piperidyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.5-1.9(8H, m), 2.4-2.6(2H, m), 2.7-3.0(5H, m),3.1-3.4(2H, m), 4.27(2H, d, J=4.6 Hz), 4.64(2H, s), 7.1-7.4(6H, m),7.51(1H, d, J=9.2 Hz), 7.73(1H, d, J=8.4 Hz), 10.79(1H, br s), 11.83(1H,s).

Mass (APCI) m/e: 387.2 (M+H)+.

EXAMPLE 35

3-[(4-hydroxy-4-phenyl-1-piperidyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-1.9(8H, m), 2.4-2.6(2H, m), 2.75-2.95(2H, m),3.1-3.4(2H, m), 4.42(2H, d, J=4.4 Hz), 7.2-7.5(6H, m), 7.59(1H, d, J=8.4Hz), 7.76(1H, d, J=8.4 Hz), 11.29(1H, br s), 11.85(1H, s).

Mass (APCI) m/e: 389.2 (M+H)+.

EXAMPLE 36

3-(1,4′-bipiperidin-1′-ylmethyl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinonedihydrochloride

¹H NMR (DMSO-d₆) δ: 1.2-1.9(10H, m), 2.0-2.7(6H, m), 2.7-3.2(9H, m),3.2-3.6(2H, m), 4.33(2H, s), 7.34(1H, s), 7.44(1H, d, J=8.0 Hz),7.76(1H, d, J=8.0 Hz), 10.54(1H, br s), 10.84(1H, br s), 11.85(1H, s).

Mass (APCI) m/e: 380.4 (M+H)+.

EXAMPLE 37

3-[(4-bromo-1-piperidyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-1.9(6H, m), 2.0-2.2(2H, m), 2.3-2.6(2H, m),2.8-3.4(5H, m), 4.30(2H, d, J=2.8 Hz), 4.44(2H, d, J=4.8 Hz), 7.36(1H,s), 7.53(1H, d, J=8.3 Hz), 7.74(1H, d, J=8.3 Hz), 11.42(1H, br s),11.85(1H, s).

Mass (APCI) m/e: 375.1, 377.1 (M+H)+.

EXAMPLE 38

3-{[4-(5-chloro-2-pyridyl)-1-piperazinyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonedihydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-1.9(6H, m), 2.4-2.6(2H, m), 2.7-2.9(2H, m),3.0-3.7(6H, m), 4.40(2H, s), 6.99(1H, d, J=9.2 Hz), 7.34(1H, s),7.5-7.8(3H, m), 8.17(1H, d, J=2.6 Hz), 11.76(1H, br s), 11.85(1H, s).

Mass (APCI) m/e: 409.3 (M+H)+.

EXAMPLE 39

3-{[4-(2-thienyl)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.6-2.3(4H, m), 2.8-3.5(5H, m), 4.36(2H, d, J=4.9Hz), 6.85-7.05(6H, m), 7.35-7.80(4H, m), 10.93(1H, br s), 11.86(1H, s).

Mass (APCI) m/e: 379.3(M+H)+.

EXAMPLE 40

Under a nitrogen atmosphere,3-bromo-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (150 mg) wasdissolved in dioxane (10 ml) in 20 ml of sealed tube. To this solutionwere added sodium tert-butoxide (1.04 g),2,2′-bis(diphenylphophino)-1,1′-binaphthyl (101 mg) andtris(dibenzylideneacetone)dipalladium (0) (49 mg) successively. Themixture was stirred for 36 hours at 140° C. in sealed tube and thencooled to room temperature. The crude mixture was poured into a mixtureof water and chloroform. The separated organic layer was washed withbrine and dried over magnesium sulfate. After evaporation of thesolvent, the residue was purified by column chromatography on silica-geleluting with a mixture of DCM and acetone and then a mixture ofchloroform and MeOH to give a thin yellow powder. A suspension of theyellow powder in MeOH (2 ml) was added with 4N hydrogen chloride inEtOAc (0.5 ml) to dissolve. After removal of the solvent, the resultingprecipitate was washed with diethyl ether to give3-(diethylamino)-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride (45 mg).

IR (KBr) cm⁻¹: 3401, 1643, 1558.

¹H-NMR (DMSO-d₆) δ: 1.0-1.2(6H, m), 1.65-1.9(4H, m), 2.45-2.55(2H, m),2.7-2.9(2H, m), 3.3-3.5(4H, m), 7.15-7.75(3H, m), 11.59(1H, s).

Mass: 293.3 (M+Na)+.

EXAMPLE 41

3-Morpholin-4-yl-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (61 mg) wasobtained in a similar manner to Example 40.

IR (KBr) cm⁻¹: 3420, 1641, 1554.

¹H-NMR (DMSO-d₆) δ: 1.6-1.8(4H, m), 2.4-2.5(2H, m), 2.7-2.8(2H, m),3.1-3.2(4H, m), 3.7-3.8(4H, m), 6.68(1H, s), 6.87(1H, d, J=9.0 Hz),7.49(1H, d, J=9.0 Hz), 11.30(1H, s).

EXAMPLE 42

4-Hydroxy-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (202 mg) was addedto a solution of potassium hydroxide (63 mg) and 2-bromopyridine indimethyl sulfoxide (20 ml) at room temperature. The mixture was stirredat 130° C. for 6 hours, cooled to room temperature and then poured intoa mixture of water and EtOAc. After the pH of the solution was adjustedto 5.5 with 1N aqueous hydrogen chloride solution, an unsolvablematerial was removed by filtration. The separated organic layer from thefiltrate was washed with brine and dried over magnesium sulfate.Evaporation of the solvent gave3-(pyridin-2-yloxy)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (29 mg).

¹H-NMR (DMSO-d₆) δ: 1.65-1.9(4H, m), 2.4-2.55(2H, m), 2.75-3.0(2H, m),7.05-7.35(4H, m), 7.56(1H, dd, J=7.4, 1.7 Hz), 7.8-7.9(1H, m), 8.03(1H,dd, J=4.9, 1.3 Hz), 11.20(1H, s).

Mass: 315.2 (M+Na)+.

EXAMPLE 43

Under a nitrogen atmosphere, thiophenol (88 mg) was added to a solutionof potassium tert-butoxide (89 mg) in DMF (4 ml) at 0° C. After 10minutes, a solution of3-[(4-bromo-1-piperidyl)methyl]-7,8,9,10-tetrahydro-6(5H)-phenanthridinone(200 mg) in DMF (2 ml) was added to the solution at the sametemperature. The mixture was stirred at 60° C. for 1.5 hours and pouredinto a mixture of saturated aqueous sodium hydrogen carbonate andchloroform. The organic phase was separated and washed with water, brineand then dried over magnesium sulfate. After evaporation of the solventthe residue was purified by column chromatography on silica-gel elutingwith DCM and acetone. The active fragments were collected andevaporated. The crystalline product was collected by filtration, washedwith MeOH and dried under reduced pressure to afford3-{[4-(phenylthio)-1-piperidyl]methyl}-7,8,9,10-tetrahydro-6(5H)-phenanthridinonehydrochloride.

¹H NMR (DMSO-d₆) δ: 1.6-2.1(8H, m), 2.3-2.6(2H, m), 2.7-3.5(7H, m),4.30(2H, d, J=4.2 Hz), 7.2-7.6(7H, m), 7.75(1H, d, J=8.3 Hz), 11.07(1H,br s), 11.83(1H, s).

Mass (APCI) m/e: 405.2 (M+H)⁺.

EXAMPLE 44

3-Amino-7,8,9,10-tetrahydro-6(5H)-phenanthridinone (100 mg) wasdissolved in AcOH, and triethyl orthoformate (104 mg) and sodium azide(45.5 mg) were added successively. The mixture was stirred under refluxfor 3 hours. The solvent was evaporated in vacuo and the residue wasdiluted with a mixture of saturated aqueous sodium hydrogen carbonateand chloroform. The organic phase was separated and washed with water,brine and then dried over magnesium sulfate. Evaporation of the solventafforded 3-(1H-tetrazol-1-yl)-7,8,9,10-tetrahydro-6(5H)-phenanthridinone(55 mg).

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.4-2.6(2H, m), 2.8-2.9(2H, m),7.68(1H, dd, J=8.7, 2.2 Hz), 7.80(1H, d, J=2.2 Hz), 7.90(1H, d, J=8.7Hz), 10.18(1H, s), 11.91(1H, s).

Mass (APCI) m/e: 290.2 (M+Na)+.

EXAMPLE 45

4-Fluoro-2-(6-oxo-5,6,7,8,9,10-hexahydro-3-phenanthridinyl)-1H-isoindol-1,3(2H)-dionewas obtained in a similar manner to Reference Example 32.

¹H NMR (DMSO-d₆) δ: 1.6-1.9(4H, m), 2.3-2.5(2H, m), 2.8-2.9(2H, m),7.26(1H, dd, J=8.6, 1.9 Hz), 7.39(1H, d, J=1.9 Hz), 7.65-8.05(4H, m),11.81(1H, s).

Mass (APCI) m/e: 385.0(M+Na)⁺.

EXAMPLE 46

4-Phenylpiperazine hydrochloride (75 mg) and triethylamine (154 mg) wereadded successively to a solution of6-chloro-3-(chloromethyl)phenanthridine (100 mg) in DMF (4 ml) at roomtemperature. The whole mixture was stirred overnight at ambienttemperature. The mixture was poured into a mixture of water andchloroform and the aqueous layer was separated. The organic layer waswashed with brine and dried over magnesium sulfate. After evaporation ofthe solvent the residue was purified by column chromatography onsilica-gel eluting with DCM and acetone. After evaporation of thesolvent, the residue was suspended in a mixture of 4N aqueous HCl (3 ml)and ethanol (3 ml). The resulting crystalline product was collected byfiltration, washed with MeOH and dried under reduced pressure to afford3-[(4-phenyl-1-piperidyl)methyl]-6(5H)-phenanthridinone hydrochloride(144 mg).

¹H NMR (DMSO-d₆) δ: 1.8-2.3(4H, m), 2.80(1H, m), 3.0-3.3(2H, m),3.4-3.6(2H, m), 4.41(2H, d, J=4.7 Hz), 7.2-7.35(5H, m), 7.50(1H, s),7.65-7.75(2H, m), 7.89(1H, t, J=8.0 Hz), 8.35(1H, t, J=7.9 Hz),8.45-8.6(2H, m), 11.07(1H, br s), 11.94(1H, 1).

Mass (APCI) m/e: 369.3(M+H)+.

The compounds in the following Examples 47 to 62 were obtained in asimilar manner to Example 46.

EXAMPLE 47

3-[(4-phenyl-3,6-dihydro-1(2H)-pyridyl)methyl]-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 2.6-3.1(2H, m), 3.5-4.0(4H, m), 4.51(2H, s),6.17(1H, s), 7.0-7.5(6H, m), 7.6-7.75(2H, m), 7.8-7.9(1H, m), 8.35(1H,d, J=7.9 Hz), 8.5-8.6(2H, m), 11.1(1H, br s), 11.94(1H, s). Mass (APCI)m/e: 367.4 (M+H)+.

EXAMPLE 48

3-[(4-phenyl-1-piperazinyl)methyl]-6(5H)-phenanthridinone hydrochloride

¹H NMR (DMSO-d₆) δ: 3.1-3.5(6H, m), 3.7-3.9(2H, m), 4.48(2H, s),6.86(1H, t, J=7.2 Hz), 6.99(1H, d, J=8.1 Hz), 7.2-7.3(2H, m), 7.51(1H,s), 7.65-7.75(2H, m), 7.89(1H, t, J=7.0 Hz), 8.34(1H, d, J=7.9 Hz),8.45-8.60(2H, m), 11.60(1H, br s), 11.95(1H, s).

Mass (APCI) m/e: 370.4 (M+H)+.

EXAMPLE 49

3-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-6 (5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 3. 1-3.8(8H, m), 4.48(2H, s), 6.95-7. 15(4H, m),7.51(1H, s), 7.65-7.75(2H, m), 7.85-7.95(1H, m), 8.34(1H, d, J=7.9 Hz),8.45-8.60(2H, m), 11.58(1H, br s), 11.95(1H, s).

Mass (APCI) m/e: 388.3(M+H)+.

EXAMPLE 50

3-{[4-(2-pyridyl)-1-piperidyl]methyl}-6(5H) -phenanthridinonedihydrochloride

¹H NMR (DMSO-d₆) δ: 2.2-2.4(4H, m), 3.1-3.6(4H, m), 4.44(2H, d, J=3.3Hz), 7.12(1H, s), 7.35-7.95(5H, m), 8.33(1H, d, J=7.8 Hz), 8.45-8.60(3H,m), 8.79(1H, d, J=5.2 Hz), 11.48(1H, br s), 11.94(1H, s).

Mass (APCI) m/e: 370.3(M+H)+.

EXAMPLE 51

3-{[4-(4-nitrophenyl)-1-piperazinyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 3.1-3.8(6H, m), 4.1-4.3(2H, m), 4.46(2H, s),7.10(2H, d, J=9.3 Hz), 7.47(1H, s), 7.6-7.75(2H, m), 7.89(1H, t, J=7.1Hz), 8.12(2H, d, J=9.3 Hz), 8.34(1H, d, J=7.8 Hz), 8.45-8.60(2H, m),11.50(1H, br s), 11.95(1H, s).

Mass (APCI) m/e: 437.2(M+Na)+.

EXAMPLE 52

3-{[4-(5-chloro-2-pyridyl)-1-piperazinyl]methyl}-6(5H)-phenanthridinonedihydrochloride

¹H NMR (DMSO-d₆) δ: 3.0-3.5(6H, m), 4.2-4.6(2H, m), 4.57(2H, s),6.99(1H, d, J=9.1 Hz), 7.47(1H, s), 7.65-7.75(3H, m), 7.89(1H, t, J=7.0Hz), 8.17(1H, d, J=9.3 Hz), 8.34(1H, d, J=7.8 Hz), 8.45-8.60(2H, m),11.69(1H, br s), 11.94(1H, s).

Mass (APCI) m/e: 405.2(M+H)+.

EXAMPLE 53

3-{[4-(4-chlorophenyl)-1-piperidyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 2.00(4H, m), 2.83(1H, m), 3.13(2H, m), 3.65(2H, m),4.40(2H, s), 7.26(1H, d, J=8.4 Hz), 7.40(1H, d, J=8.4 Hz), 7.47(1H, s),7.61-7.73(2H), 7.90(1H, t, J=7.2 Hz), 8.34(1H, d, 7.6 Hz),8.49-8.60(2H), 10.87(1H, brs), 11.94(1H, s).

Mass (APCI) m/e: 403 (M+H)+.

EXAMPLE 54

3-{[4-(4-methoxyphenyl)-1-piperidyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.90-1.93(2H, m), 2.03-2.09(2H, m), 2.74(1H, m),3.08-3.11(2H, m), 3.42-3.51(2H, m), 3.72(3H, s), 4.40(2H, s), 6.88(2H,d, J=8.6 Hz), 7.14(2H, d, J=8.6 Hz), 7.49(1H, s), 7.64-7.71(2H, m),7.89(1H, t, J=7.8 Hz), 8.34(1H, d, J=7.8 Hz), 8.51(1H, d, J=8.4 Hz),8.57(1H, d, J=8.4 Hz), 10.94(1H, brs), 11.92(1H, s).

Mass (APCI) m/e: 399(M+H)+.

EXAMPLE 55

3-{[4-(4-fluorophenyl)-1-piperidyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.98(4H), 2.83(1H, m), 3.13(2H, m), 3.48(2H, m),4.40(2H, s), 7.11-7.31(4H, m), 7.49(1H, s), 7.64-7.73(2H), 7.86(1H, t,J=7.0 Hz), 8.35(1H, dd, J=1.0, 8.0 Hz), 8.50-8.60(2H), 1.00(1H, brs),11.95(1H, s).

Mass (APCI) m/e: 387(M+H)+.

EXAMPLE 56

3-[4-(4-hydroxy-4-phenyl-1-piperidyl)methyl]-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.75-3.41(6H), 4.48(2H, s), 7.22-7.50(6H, m),7.62-7.69(2H, m), 7.90(1H, t, J=7.0 Hz), 8.34(1H, d, J=6.8 Hz),8.50-8.60(2H, m), 10.87(1H, brs), 11.95(1H, s).

Mass (APCI) m/e: 385 (M+H)+.

EXAMPLE 57

3-{[4-(4-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 2.70-2.88(2H), 3.38-3.80(4H), 4.51(2H, s), 6.22(1H,s), 7.42-7.52(5H, m), 7.69(2H, t, J=7.8 Hz), 7.86-7.94(1H, m), 8.35(1H,dd, J=1.2 Hz, 7.8 Hz), 8.50-8.60(2H, m), 11.22(1H, brs), 11.95(1H, s).

EXAMPLE 58

3-{[4-(4-methylphenyl)-3,6-dihydro-1(2H)-pyridyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 2.29(3H, s), 2.70-2.89(2H,m), 3.37(1H), 3.60(1H, m),3.80(2H), 4.50(2H, s), 6.13(1H, s), 7.19(1H, d, J=8.2 Hz), 7.37(1H,J=8.2 Hz), 7.53(1H, s), 7.64-7.73(2H, m), 7.86-7.94(1H, m), 8.35, (1H,dd, J=2.0, 7.4 Hz), 8.50-8.60(2H, m), 11.16(1H, brs), 11.94(1H, s).

EXAMPLE 59

3-(1,4′-bipiperidin-1′-ylmethyl)-6(5H)-phenanthridinone dihydrochloride

¹H NMR (DMSO-d₆) δ: 1.23-1.38(2H), 1.60-1.81(5H), 2.00-2.27(4H),2.94-3.05(4H), 3.20-3.49(4H), 4.37(2H, s), 7.44(1H, s), 7.58(1H, d,J=7.8 Hz), 7.65-7.93(2H, m), 8.34(1H, d, J=7.8 Hz), 8.47-8.60(2H),10.72(1H, brs), 11.07(1H, brs), 11.93(1H, s).

EXAMPLE 60

3-(1-piperidylmethyl)-6(5H)-phenanthridinone

¹H NMR (DMSO-d₆) δ: 1.40-1.41(2H, m), 1.50-1.53(4H, m), 2.36(4H, brs),3.49(2H, s), 7.19(1H, d, J=8.2 Hz), 7.32(1H, s), 7.62(1H, t, J=8.0 Hz),7.84(1H, t, J=8.0 Hz), 8.30-8.33(2H, m), 8.47(1H, d, J=8.2 Hz) 11.63(1H,brs)

EXAMPLE 61

3-{[(3S,5S)-3,5-dimethyl-4-morpholinyl]methyl}-6(5H)-phenanthridinonehydrochloride

¹H NMR (DMSO-d₆) δ: 1.31-1.41(6H, m), 3.19-3.22(1H, m), 3.62-3.72(3H),3.92-4.03(2H), 4.15-4.26(1H, m), 4.80(1H, dd, J=3.5, 13.6 Hz), 7.51(1H,s), 7.68(1H, t, J=7.5 Hz), 7.80-7.93(2H), 8.34(1H, d, J=8.8 Hz),8.49-8.59(2H), 11.23(1H, brs), 11.87(1H, s)

EXAMPLE 62

3-(4-morpholinylmethyl)-6(5H)-phenanthridinone hydrochloride

¹H NMR (DMSO-d₆) δ: 3.1-4.1(4H, m), 4.35(2H, s), 7.48(1H, d, J=1.2 Hz),7.6-7.8(2H, m), 7.89(1H, td, J=7.6, 1.4 Hz), 8.34(1H, dd, J=7.9, 1.2Hz), 8.49(1H, d, J=8.4 Hz), 8.57(1H, d, J=8.1 Hz).

Mass (APCI) m/e: 295.3 (M+H)+.

EXAMPLE 63

3-{[4-(5-methyl-2-pyridyl)-1-piperidyl]methyl}-6(5H)-phenanthridinonewas obtained in a similar manner to Example 2.

¹H NMR (DMSO-d₆) δ: 1.8-1.9(4H, m), 2.1-2.2(2H, m), 2.24(3H, s),2.6-2.8(1H, m), 3.4-3.6(2H, m), 3.56(2H, s), 7.15-7.25(2H, m), 7.37(1H,s), 7.48-7.85(3H, m), 8.25-8.50(4H, m), 11.63(1H, s).

Mass (APCI) m/e: 384.2(M+H)+.

1. A compound of the formula (I):

wherein ring A is a carbocyclic group, R¹ is hydrogen or a halogen atomor a lower alkyl group, R² is a di(lower)alkylamino group orN-containing heterocyclic group, among which the N-containingheterocyclic group may be substituted with one or more substituent(s), Yis an oxygen or sulfur atom, n is an integer from 0 to 2, and m is aninteger from 0 to 4, or its prodrug, or their salt.
 2. A compound ofclaim 1, wherein ring A is a cyclo(lower)alkane ring or aromatichydrocarbon ring, R¹ is hydrogen or a halogen atom, R² is adi(lower)alkylamino group, a N-containing heterocyclic group, amongwhich the N-containing heterocyclic group may be substituted with one ormore substituent(s), Y is an oxygen or sulfur atom, n is an integer of 0or 1, and m is an integer from 0 to 4, or a salt thereof.
 3. A compoundof claim 2, wherein R² is tetrahydropyridyl, pyridyl, piperidyl,piperazinyl, morpholinyl or pyrido[3,4-b]indolyl, tetrazolyl,isoindolidinyl, each of which may be substituted with one or moresubstituent(s).
 4. A compound of claim 3, wherein the ring A is acyclohexane ring and R¹ is hydrogen atom.
 5. A compound of claim 4,wherein Y is an oxygen atom and m is an integer from 0 to
 3. 6. Acompound of claim 3, wherein the ring A is a benzene ring, n is 0 and mis an integer 1 to
 4. 7. A compound of claim 6, wherein R² ismorpholinyl and m is
 1. 8. A pharmaceutical composition comprising acompound of the formula (I):

wherein the ring A, R¹, R², Y, n and m are the same meanings as definedin claim 1, its prodrug or a pharmaceutically acceptable salt thereof inadmixture with a pharmaceutically acceptable carrier.
 9. Thepharmaceutical composition of claim 8 which is used for treating orpreventing diseases ascribed by excess activation of PARP.
 10. Thepharmaceutical composition of claim 9 wherein diseases ascribed byexcess activation of PARP are tissue damage resulting from cell damageor death due to necrosis or apoptosis; neural tissue damage resultingfrom ischemia and reperfusion injury, neurological disorders andneurodegenerative diseases; neurodegenerative diseases; head trauma;stroke; Alzheimer's disease; Perkinson's disease; epilepsy; AmyotrophicLateral Scleosis (ALS); Huntington's disease; schizopherenia; chronicpain; ischemia and neuronal loss following hypoxia; hypoglycemia;ischemia; trauma; nervous insult; previously ischemic heart or skeletonmuscle tissue; radiosensitizing hypoxic tumor cells; tumor cells fromrecovering from potentially lethal damage of DNA after radiationtherapy; skin aging; atheroscleosis; osteoarthritis; osteoporosis;muscular dystrophy; degenerative diseases of skeletal muscle involvingreplicative senescence; age-related macular degeneration; immunesenescence; AIDS; and other immune senescencediseases; inflammatorybowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock;septic shock; and/or tumor.
 11. A method for treating or preventingdiseases ascribed by excess activation of PARP by administering acompound of the formula (I):

wherein the ring A, R¹, R², Y, n and m are the same meanings as definedin claim 1, its prodrug, or a pharmaceutically acceptable salt thereofin an effective amount to inhibit PARP activity, to human being or ananimal who needs to be treated or prevented.
 12. A use of the compoundof claim 1 as a medicament.
 13. A use of the compound of claim 1 forpreparing a medicament for treating or preventing diseases ascribed byexcess activation of PARP.
 14. The use of claim 13 wherein diseasesascribed by excess activation of PARP are tissue damage resulting fromcell damage or death due to necrosis or apoptosis; neural tissue damageresulting from ischemia and reperfusion injury, neurological disordersand neurodegenerative diseases; neurodegenerative diseases; head trauma;stroke; Alzheimer's disease; Perkinson's disease; epilepsy; AmyotrophicLateral Scleosis (ALS); Huntington's disease; schizopherenia; chronicpain; ischemia and neuronal loss following hypoxia; hypoglycemia;ischemia; trauma; nervous insult; previously ischemic heart or skeletonmuscle tissue; radiosensitizing hypoxic tumor cells; tumor cells fromrecovering from potentially lethal damage of DNA after radiationtherapy; skin aging; atheroscleosis; osteoarthritis; osteoporosis;muscular dystrophy; degenerative diseases of skeletal muscle involvingreplicative senescence; age-related macular degeneration; immunesenescence; AIDS; and other immune senescencediseases; inflammatorybowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock;septic shock; and tumor.